ES2235187T3 - NEUROACTIVE STEROIDS OF THE ANDROSTAN AND PREGNAN SERIES. - Google Patents
NEUROACTIVE STEROIDS OF THE ANDROSTAN AND PREGNAN SERIES.Info
- Publication number
- ES2235187T3 ES2235187T3 ES96919372T ES96919372T ES2235187T3 ES 2235187 T3 ES2235187 T3 ES 2235187T3 ES 96919372 T ES96919372 T ES 96919372T ES 96919372 T ES96919372 T ES 96919372T ES 2235187 T3 ES2235187 T3 ES 2235187T3
- Authority
- ES
- Spain
- Prior art keywords
- hydroxy
- methoxy
- androstane
- ethynyl
- compound according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000003431 steroids Chemical class 0.000 title abstract description 54
- JWMFYGXQPXQEEM-WZBAXQLOSA-N pregnane Chemical class C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](CC)[C@@]1(C)CC2 JWMFYGXQPXQEEM-WZBAXQLOSA-N 0.000 title abstract description 7
- QZLYKIGBANMMBK-UGCZWRCOSA-N 5α-Androstane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CCC[C@@]2(C)CC1 QZLYKIGBANMMBK-UGCZWRCOSA-N 0.000 title abstract description 6
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 15
- 230000036506 anxiety Effects 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims description 114
- 230000000694 effects Effects 0.000 claims description 49
- -1 amino, thio, sulfinyl Chemical group 0.000 claims description 48
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 33
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 22
- 125000000304 alkynyl group Chemical group 0.000 claims description 21
- 229910052799 carbon Inorganic materials 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 125000003342 alkenyl group Chemical group 0.000 claims description 20
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 159000000000 sodium salts Chemical class 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 16
- 241001465754 Metazoa Species 0.000 claims description 14
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 14
- 125000004429 atom Chemical group 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 230000007958 sleep Effects 0.000 claims description 12
- 125000004122 cyclic group Chemical group 0.000 claims description 11
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 125000005016 hydroxyalkynyl group Chemical group 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 230000035882 stress Effects 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- JLNJJWYVMIIQDU-ZUFCDVJMSA-N C(#C)C[C@@]12[C@H](CC[C@H]1[C@@H]1CC[C@@H]3C[C@@H](CC[C@]3(C)[C@H]1CC2)O)OC Chemical compound C(#C)C[C@@]12[C@H](CC[C@H]1[C@@H]1CC[C@@H]3C[C@@H](CC[C@]3(C)[C@H]1CC2)O)OC JLNJJWYVMIIQDU-ZUFCDVJMSA-N 0.000 claims description 6
- 208000019022 Mood disease Diseases 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- 206010022437 insomnia Diseases 0.000 claims description 6
- 125000000468 ketone group Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 230000036385 rapid eye movement (rem) sleep Effects 0.000 claims description 6
- 206010002091 Anaesthesia Diseases 0.000 claims description 5
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 230000037005 anaesthesia Effects 0.000 claims description 5
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 5
- 125000004494 ethyl ester group Chemical group 0.000 claims description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 5
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 4
- IKRVSZMOFPIGAA-YRCTWBNTSA-N C(#C)C[C@@]12[C@H](CC[C@H]1[C@@H]1CC[C@@H]3CCCC[C@]3(C)[C@H]1CC2)OC Chemical compound C(#C)C[C@@]12[C@H](CC[C@H]1[C@@H]1CC[C@@H]3CCCC[C@]3(C)[C@H]1CC2)OC IKRVSZMOFPIGAA-YRCTWBNTSA-N 0.000 claims description 3
- 229930194542 Keto Natural products 0.000 claims description 3
- 125000002905 alkanoylamido group Chemical group 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 3
- 125000004385 trihaloalkyl group Chemical group 0.000 claims description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 claims description 2
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 claims description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- 125000002015 acyclic group Chemical group 0.000 claims description 2
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 2
- 150000001371 alpha-amino acids Chemical class 0.000 claims description 2
- 235000008206 alpha-amino acids Nutrition 0.000 claims description 2
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 2
- 125000005014 aminoalkynyl group Chemical group 0.000 claims description 2
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 2
- 125000005335 azido alkyl group Chemical group 0.000 claims description 2
- 125000004982 dihaloalkyl group Chemical group 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims 4
- 150000003857 carboxamides Chemical class 0.000 claims 4
- 125000001475 halogen functional group Chemical group 0.000 claims 4
- 230000002265 prevention Effects 0.000 claims 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- 208000013200 Stress disease Diseases 0.000 claims 1
- 230000002920 convulsive effect Effects 0.000 claims 1
- 125000004970 halomethyl group Chemical group 0.000 claims 1
- 239000002555 ionophore Substances 0.000 claims 1
- 230000000236 ionophoric effect Effects 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 claims 1
- 125000003107 substituted aryl group Chemical group 0.000 claims 1
- 125000004953 trihalomethyl group Chemical group 0.000 claims 1
- 206010001497 Agitation Diseases 0.000 abstract description 17
- 210000004556 brain Anatomy 0.000 abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
- 230000001037 epileptic effect Effects 0.000 abstract description 5
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical class [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 201
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 186
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 119
- 239000000203 mixture Substances 0.000 description 118
- 239000000243 solution Substances 0.000 description 109
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 102
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 67
- 235000019439 ethyl acetate Nutrition 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 44
- 239000007787 solid Substances 0.000 description 41
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 239000000186 progesterone Substances 0.000 description 35
- 229960003387 progesterone Drugs 0.000 description 35
- 239000002904 solvent Substances 0.000 description 32
- 238000010828 elution Methods 0.000 description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- 239000012043 crude product Substances 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 238000000034 method Methods 0.000 description 26
- 239000000047 product Substances 0.000 description 25
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 24
- 239000012044 organic layer Substances 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 24
- 229910002027 silica gel Inorganic materials 0.000 description 24
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 23
- 235000019341 magnesium sulphate Nutrition 0.000 description 23
- 238000012360 testing method Methods 0.000 description 23
- 239000012267 brine Substances 0.000 description 22
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
- 238000003756 stirring Methods 0.000 description 21
- 238000001035 drying Methods 0.000 description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 206010036618 Premenstrual syndrome Diseases 0.000 description 18
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 230000000949 anxiolytic effect Effects 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 12
- VTBHBNXGFPTBJL-UHFFFAOYSA-N 4-tert-butyl-1-sulfanylidene-2,6,7-trioxa-1$l^{5}-phosphabicyclo[2.2.2]octane Chemical compound C1OP2(=S)OCC1(C(C)(C)C)CO2 VTBHBNXGFPTBJL-UHFFFAOYSA-N 0.000 description 11
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- 201000009916 Postpartum depression Diseases 0.000 description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
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- 239000011780 sodium chloride Substances 0.000 description 11
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Classifications
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- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
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- A—HUMAN NECESSITIES
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- A61P25/24—Antidepressants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0007—Androstane derivatives not substituted in position 17
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- C—CHEMISTRY; METALLURGY
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- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
- C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
- C07J1/0029—Ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0055—Estrane derivatives not substituted in position 17
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
- C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
- C07J1/0077—Ethers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
Landscapes
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- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Anesthesiology (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
LA INVENCION TRATA DE DERIVADOS 3 AL - HIDROXI, SUSTITUIDOS (O NO) EN LA POSICION 17 DE LA SERIE DEL ANDROSTANO Y DE DERIVADOS 3 AL} - HIDROXI, SUSTITUIDOS EN LA POSICION 21 DE LA SERIE DEL PREGNANO. ESTOS DERIVADOS SON CAPACES DE ACTUAR EN UN SITIO RECIENTEMENTE IDENTIFICADO SOBRE EL GRC, MODULANDO CON ELLO LA EXCITABILIDAD CEREBRAL DE UNA FORMA QUE ALIVIA EL ESTRES, LA ANSIEDAD, EL INSOMNIO, LOS TRASTORNOS DEL CARACTER QUE PUEDEN SER CURADO POR AGENTES GRC - ACTIVOS (TAL COMO LA DEPRESION) Y LA ACTIVIDAD EPILEPTICA. LOS DERIVADOS ESTEROIDEOS DE ESTA INVENCION SON LOS QUE PRESENTAN LA FORMULA ESTRUCTURAL GENERAL (I), EN LA CUAL R, R SUB,1}, R SUB,2}, R SUB,3}, R SUB,4}, R SUB,5}, R SUB,6}, R SUB,7}, R SUB,8}, R SUB,9} Y R SUB,10} SE DEFINEN MAS A FONDO EN LA PRESENTE, Y LAS LINEAS DISCONTINUAS SON ENLACES SENCILLOS O DOBLES. LA ESTRUCTURA INCLUYE ANDROSTANOS, PREGNANOS (R SUB,4} = METILO), 19 - NORANDROSTANOS Y NORPREGNANOS (R SUB,4} = H).THE INVENTION TRIES OF DERIVATIVES 3 TO - HYDROXY, REPLACED (OR NOT) IN POSITION 17 OF THE ANDROSTAN SERIES AND OF DERIVATIVES 3 TO} - HYDROXI, REPLACED IN POSITION 21 OF THE PREGNAN SERIES. THESE DERIVATIVES ARE ABLE TO ACT ON A RECENTLY IDENTIFIED SITE ON THE GRC, MODULATING WITH IT THE BRAIN EXCITABILITY IN A WAY THAT RELIEFS STRESS, ANXIETY, INSOMNIUM, CHARACTER DISORDERS THAT CAN BE CURED BY GRC AGENTS - ACTIVE GRC - AS DEPRESSION) AND EPILEPTIC ACTIVITY. THE STEROID DERIVATIVES OF THIS INVENTION ARE THOSE THAT PRESENT THE GENERAL STRUCTURAL FORMULA (I), IN WHICH R, R SUB, 1}, R SUB, 2}, R SUB, 3}, R SUB, 4}, R SUB, 5}, R SUB, 6}, R SUB, 7}, R SUB, 8}, R SUB, 9} YR SUB, 10} ARE DETERMINED FUNDING THIS TIME, AND THE DISCONTINUOUS LINES ARE SIMPLE OR DOUBLE LINKS. THE STRUCTURE INCLUDES ANDROSTANS, PREGNANS (R SUB, 4} = METHYL), 19 - NORANDROSTANS AND NORPREGNANS (R SUB, 4} = H).
Description
Esteroides neuroactivos de las series del androstano y el pregnano.Neuroactive Steroids Series Androstane and Pregnan.
Esta solicitud es una continuación en parte de la Solicitud Nº 08/467.404, presentada el 6 de Junio de 1995, cuyo contenido se incorpora en su totalidad mediante referencia.This request is a continuation in part of the Application No. 08 / 467,404, filed on June 6, 1995, whose Content is incorporated in its entirety by reference.
La presente invención se dirige a nuevos derivados esteroideos de las series del androstano y el pregnano, así como a composiciones farmacéuticas y métodos para modular la excitabilidad cerebral. Más particularmente, la invención se refiere a derivados 3\alpha-hidroxi, 17-(no)substituidos de la serie del androstano y a derivados substituidos en 21 de la serie del pregnano.The present invention is directed to new Steroid derivatives of the Androstane and Pregnan series, as well as pharmaceutical compositions and methods to modulate the brain excitability. More particularly, the invention relates to 3α-hydroxy derivatives, 17- (not) substituted androstane series and derivatives replaced in 21 of the pregnan series.
La excitabilidad cerebral se define como el nivel de estimulación de un animal, un continuo que varía desde coma hasta convulsiones, y está regulada por diversos neurotransmisores. En general, los neurotransmisores son responsables de regular la conductancia de iones a través de membranas neuronales. En reposo, la membrana neuronal posee un potencial (o voltaje de membrana) de aproximadamente -80 mV, siendo negativo el interior de la célula con respecto al exterior de la célula. El potencial (voltaje) es el resultado del equilibrio iónico (K^{+}, Na^{+}, Cl^{-}, aniones orgánicos) a través de la membrana semipermeable neuronal. Los neurotransmisores se almacenan en vesículas presinápticas y se liberan bajo la influencia de potenciales de acción neuronal. Cuando se libera en la hendidura sináptica, un transmisor químico excitador tal como acetilcolina provocará la despolarización de la membrana (cambio de potencial desde -80 mV hasta -50 mV). Este efecto está mediado por receptores nicotínicos postsinápticos que son estimulados por acetilcolina para incrementar la permeabilidad de la membrana a iones Na^{+}. El potencial de membrana reducido estimula la excitabilidad neuronal en la forma de un potencial de acción postsináptica.Brain excitability is defined as the level of stimulation of an animal, a continuum that varies from coma up to seizures, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the ion conductance through neuronal membranes. Resting, The neuronal membrane has a potential (or membrane voltage) of approximately -80 mV, the interior of the cell being negative with with respect to the outside of the cell. The potential (voltage) is the result of ionic equilibrium (K +, Na +, Cl -, organic anions) through the neuronal semipermeable membrane. Neurotransmitters are stored in presynaptic vesicles and are released under the influence of neuronal action potentials. When released in the synaptic cleft, a chemical transmitter exciter such as acetylcholine will cause depolarization of the membrane (potential change from -80 mV to -50 mV). This effect is mediated by postsynaptic nicotinic receptors that are stimulated by acetylcholine to increase permeability from the membrane to Na + ions. The reduced membrane potential stimulates neuronal excitability in the form of a potential for postsynaptic action.
En el caso del complejo receptor de GABA (GRC), el efecto sobre la excitabilidad cerebral es mediado por GABA, un neurotransmisor. El GABA tiene una profunda influencia sobre la excitabilidad cerebral global debido a que hasta 40% de las neuronas del cerebro utilizan GABA como un neurotransmisor. El GABA regula la excitabilidad de neuronas individuales regulando la conductancia de iones cloruro a través de la membrana neuronal. El GABA interactúa con su sitio de reconocimiento sobre el GRC para facilitar el flujo de iones cloruro descendentemente hasta un gradiente electroquímico del GRC en la célula. Un incremento intracelular en los niveles de este anión provoca la hiperpolarización del potencial de transmembrana, haciendo la neurona menos susceptible a entradas excitadoras (es decir, excitabilidad neuronal reducida). En otras palabras, cuanto más alta es la concentración de ion cloruro en la neurona, menor es la excitabilidad cerebral (el nivel de estimulación).In the case of the GABA receptor complex (GRC), the effect on brain excitability is mediated by GABA, a neurotransmitter GABA has a profound influence on the global brain excitability because up to 40% of Brain neurons use GABA as a neurotransmitter. The GABA regulates the excitability of individual neurons by regulating the chloride ion conductance through the neuronal membrane. He GABA interacts with its GRC recognition site to facilitate the flow of chloride ions downwards to a electrochemical gradient of the GRC in the cell. An increment intracellular in the levels of this anion causes the hyperpolarization of the transmembrane potential, making the neuron less susceptible to excitatory inputs (i.e. reduced neuronal excitability). In other words, the more high is the concentration of chloride ion in the neuron, the lower the cerebral excitability (the level of stimulation).
Está bien documentado que el GRC es responsable de la mediación de la ansiedad, la actividad convulsiva y la sedación. Así, el GABA y los fármacos que actúan como el GABA o facilitan los efectos del GABA (por ejemplo, los barbituratos y las benzodiazepinas (BZs) útiles terapéuticamente, tales como el Valium) producen sus efectos terapéuticamente útiles interactuando con sitios reguladores específicos del GRC.It is well documented that the GRC is responsible of the mediation of anxiety, seizure activity and sedation. Thus, GABA and drugs that act like GABA or facilitate the effects of GABA (for example, barbiturates and Therapeutically useful benzodiazepines (BZs), such as Valium) produce their therapeutically useful effects interacting with GRC specific regulatory sites.
La evidencia acumulada ha indicado ahora que además del sitio de unión a benzodiazepinas y barbituratos, el GRC contiene un sitio distinto para esteroides neuroactivos (Lan, N.C. y otros, Neurochem. Res. 16:347-356 (1991)). Los esteroides neuroactivos pueden presentarse endógenamente. Los esteroides neuroactivos endógenos más potentes son pregnan-20-ona reducida en 5 substituida en 3\alpha con hidroxi y pregnan-20-ona reducida en 5 substituida en 3\alpha,21 con dihidroxi, metabolitos de los esteroides hormonales progesterona y desoxicorticosterona, respectivamente. La capacidad de estos metabolitos esteroideos para alterar la excitabilidad cerebral fue reconocida en 1986 (Majewska, M.D. y otros, Science 232:1004-1007 (1986); Harrison, N.L. y otros, J. Pharmacol. Exp. Ther. 241:346-353 (1987)). Sin embargo, la utilidad terapéutica de estos metabolitos esteroideos y sus derivados (esteroides neuroactivos) no fue reconocida por los estudiosos de la especialidad debido a una comprensión incompleta de la potencia y el sitio de acción de estos esteroides neuroactivos. La invención de los solicitantes se refiere en parte a una aplicación farmacéutica del conocimiento obtenido a partir de una comprensión más desarrollada de la potencia y el sitio de acción de ciertos compuestos esteroideos.Accumulated evidence has now indicated that in addition to the benzodiazepine and barbiturate binding site, the GRC contains a distinct site for neuroactive steroids (Lan, NC et al., Neurochem. Res. 16 : 347-356 (1991)). Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are pregnan-20-one reduced in 5 substituted in 3α with hydroxy and pregnan-20-one reduced in 5 substituted in 3α, 21 with dihydroxy, hormonal steroid metabolites progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, MD et al., Science 232 : 1004-1007 (1986); Harrison, NL et al., J. Pharmacol. Exp. Ther. 241 : 346- 353 (1987)). However, the therapeutic usefulness of these steroidal metabolites and their derivatives (neuroactive steroids) was not recognized by specialty scholars due to an incomplete understanding of the potency and site of action of these neuroactive steroids. The invention of the applicants refers in part to a pharmaceutical application of the knowledge obtained from a more developed understanding of the potency and site of action of certain steroid compounds.
Se ha demostrado que la hormona ovárica progesterona y sus metabolitos tienen efectos profundos sobre la excitabilidad cerebral (Backstrom, T. y otros, Acta Obstet. Gynecol. Scand. Suppl. 130:19-24 (1985); Pfaff, D.W. y McEwen, B.S., Science 219:808-814 (1983); Gyermek y otros, J. Med. Chem. 11:117 (1968); Lambert, J. y otros, Trends Pharmacol Sci. 8:224-227 (1987)). Los niveles de progesterona y sus metabolitos varían con las fases del ciclo menstrual. Se ha documentado bien que la progesterona y sus metabolitos disminuyen antes del comienzo de la menstruación. La recurrencia mensual de ciertos síntomas físicos antes del comienzo de la menstruación también se ha documentado bien. Estos síntomas, que se han asociado con el síndrome premenstrual (PMS), incluyen estrés, ansiedad y jaquecas migrañosas (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2ª edición, Chicago Yearbook, Chicago (1984)). Las pacientes con PMS tienen una recurrencia mensual de síntomas que están presentes en periodos premenstruales y ausentes en períodos postmenstruales.Ovarian hormone progesterone and its metabolites have been shown to have profound effects on brain excitability (Backstrom, T. et al., Acta Obstet. Gynecol. Scand. Suppl. 130 : 19-24 (1985); Pfaff, DW and McEwen, BS, Science 219 : 808-814 (1983); Gyermek et al., J. Med. Chem. 11 : 117 (1968); Lambert, J. et al., Trends Pharmacol Sci. 8 : 224-227 (1987)). The levels of progesterone and its metabolites vary with the phases of the menstrual cycle. It has been well documented that progesterone and its metabolites decrease before the onset of menstruation. The monthly recurrence of certain physical symptoms before the onset of menstruation has also been well documented. These symptoms, which have been associated with premenstrual syndrome (PMS), include stress, anxiety and migraine headaches (Dalton, K., Premenstrual Syndrome and Progesterone Therapy , 2nd edition, Chicago Yearbook, Chicago (1984)). Patients with PMS have a monthly recurrence of symptoms that are present in premenstrual periods and absent in postmenstrual periods.
De un modo similar, una reducción en la progesterona también se ha correlacionado temporalmente con un incremento en la frecuencia de ataques en mujeres epilépticas, es decir, epilepsia catamenial (Laidlaw, J., Lancet, 1235-1237 (1956)). Se ha observado una correlación más directa con una reducción en metabolitos de progesterona (Rosciszewska y otros, J. Neurol. Neurosurg. Psych. 49:47-51 (1986)). Además, para pacientes con epilepsia de pequeño mal generalizada primaria, la incidencia temporal de ataques se ha correlacionado con la incidencia de los síntomas del síndrome premenstrual (Backstrom, T. y otros, J. Psychosom. Obstet. Gynaecol. 2:8-20 (1983)). Se ha encontrado que el esteroide desoxicorticosterona es eficaz para tratar pacientes con períodos epilépticos correlacionados con sus ciclos menstruales (Aird, R.B. y Gordan, G. J. Amer. Med. Soc. 145:715-719 (1951)).Similarly, a reduction in progesterone has also been temporarily correlated with an increase in the frequency of seizures in epileptic women, that is, catamenial epilepsy (Laidlaw, J., Lancet , 1235-1237 (1956)). A more direct correlation has been observed with a reduction in progesterone metabolites (Rosciszewska et al., J. Neurol. Neurosurg. Psych. 49 : 47-51 (1986)). In addition, for patients with epilepsy of small primary generalized disease, the temporal incidence of seizures has been correlated with the incidence of premenstrual syndrome symptoms (Backstrom, T. et al., J. Psychosom. Obstet. Gynaecol. 2 : 8-20 (1983)). It has been found that the deoxycorticosterone steroid is effective in treating patients with epileptic periods correlated with their menstrual cycles (Aird, RB and Gordan, GJ Amer. Med. Soc. 145 : 715-719 (1951)).
Un síndrome también relacionado con bajos niveles
de progesterona es la depresión postnatal (PND). Inmediatamente
después del nacimiento, los niveles de progesterona disminuyen
drásticamente conduciendo al comienzo de la
PND. Los
síntomas de la PND varían desde depresión leve hasta psicosis que
requiere hospitalización. La PND también está asociada con ansiedad
e irritabilidad intensas. La depresión asociada con PND no es
susceptible de tratamiento mediante antidepresivos clásicos y las
mujeres que experimentan PND muestran una incidencia incrementada
de PMS (Dalton, K., Premenstrual Syndrome and Progesterone
Therapy, 2ª edición, Chicago Yearbook, Chicago (1984)).A syndrome also related to low levels of progesterone is postnatal depression (PND). Immediately after birth, progesterone levels decrease dramatically leading to the onset of
PND The symptoms of PND vary from mild depression to psychosis that requires hospitalization. PND is also associated with intense anxiety and irritability. Depression associated with PND is not susceptible to treatment by classic antidepressants and women who experience PND show an increased incidence of PMS (Dalton, K., Premenstrual Syndrome and Progesterone Therapy , 2nd edition, Chicago Yearbook, Chicago (1984)).
Colectivamente, estas observaciones implican un papel crucial para la progesterona y la desoxicorticosterona y más específicamente sus metabolitos en la regulación homeostática de la excitabilidad cerebral, que se manifiesta como un incremento en la actividad convulsiva o síntomas asociados con la epilepsia catamenial, PMS y PND. La correlación entre niveles reducidos de progesterona y los síntomas asociados con PMS, PND y epilepsia catamenial (Backstrom, T. y otros, Psychosom. Obstet. Gynaecol. 2:8-20 (1983)); Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2ª edición, Chicago Yearbook, Chicago (1984)) ha provocado el uso de progesterona en su tratamiento (Mattson y otros, "Medroxyprogesterone therapy of catamenial epilepsy", en Advances in epileptology: XVth Epilepsy International Symposium, Raven Press, Nueva York (1984), pp. 279-282 y Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2ª edición, Chicago Yearbook, Chicago (1984)). Sin embargo, la progesterona no es consecuentemente eficaz en el tratamiento de los síndromes mencionados previamente. Por ejemplo, no existe una relación dosis-respuesta para la progesterona en el tratamiento de PMS (Maddocks, y otros, Obstet. Gynecol. 154:573-581 (1986); Dennerstein y otros, Brit. Med. J. 290:16-17 (1986)).Collectively, these observations imply a crucial role for progesterone and deoxycorticosterone and more specifically its metabolites in the homeostatic regulation of cerebral excitability, which manifests itself as an increase in seizure activity or symptoms associated with catamenial epilepsy, PMS and PND. The correlation between reduced levels of progesterone and the symptoms associated with PMS, PND and catamenial epilepsy (Backstrom, T. et al., Psychosom. Obstet. Gynaecol. 2 : 8-20 (1983)); Dalton, K., Premenstrual Syndrome and Progesterone Therapy , 2nd edition, Chicago Yearbook, Chicago (1984)) has caused the use of progesterone in its treatment (Mattson et al., "Medroxyprogesterone therapy of catamenial epilepsy", in Advances in epileptology: XVth Epilepsy International Symposium , Raven Press, New York (1984), pp. 279-282 and Dalton, K., Premenstrual Syndrome and Progesterone Therapy , 2nd edition, Chicago Yearbook, Chicago (1984)). However, progesterone is not consistently effective in the treatment of the previously mentioned syndromes. For example, there is no dose-response relationship for progesterone in the treatment of PMS (Maddocks, et al., Obstet. Gynecol. 154 : 573-581 (1986); Dennerstein et al., Brit. Med. J. 290 : 16 -17 (1986)).
Templeton y otros, Steroids 48:339-346 (1986) describen una reducción estereoselectiva y regioselectiva de cetonas esteroideas para formar alcoholes axiales en el carbono 3. El compuesto 17\beta-metoxi-2\beta-metil-5\alpha-androstan-3\alpha-ol se forma a partir de 17\beta-metoxi-2\alpha,3\alpha-epoxi-5\alpha-androstano.Templeton et al., Steroids 48 : 339-346 (1986) describe a stereoselective and regioselective reduction of steroid ketones to form axial alcohols in carbon 3. Compound 17? -Methoxy-2? -Methyl-5? -Androstan -3α-ol is formed from 17β-methoxy-2α, 3α-epoxy-5α-androstane.
Grieco y otros, J. Am. Chem. Soc. 11:7799-7801 (1990), describen el uso de 17\beta-metoxi-5\alpha-androstan-3\alpha-ol como un material de partida para formar conjugados que comprenden metaloporfirinas unidas a substratos esteroideos.Grieco et al., J. Am. Chem. Soc. 11 : 7799-7801 (1990), describe the use of 17β-methoxy-5α-androstan-3α-ol as a starting material for forming conjugates comprising metalloporphyrins bound to steroidal substrates.
La Patente de EE.UU. Nº 4.297.350 de Babcok y otros, expedida el 27 de Octubre de 1991, describe ampliamente 17-éteres de androstano y androsteno esteroideos y su uso como anticonceptivos masculinos.U.S. Pat. No. 4,297,350 of Babcok and others, issued on October 27, 1991, describe extensively 17-ethers of androstane and androstene steroids and their use as male contraceptives
Neef y otros, Tetrahedron Letters 21:903-906 (1980), describen el compuesto 17\beta-metoximetoxi-3\beta-(1-propinil)-5\alpha-androsten-3\alpha-ol como un producto intermedio en la formación de derivados esteroideos.Neef et al., Tetrahedron Letters 21 : 903-906 (1980), describe the compound 17β-methoxymethoxy-3β- (1-propynyl) -5α-androsten-3α-ol as an intermediate in Steroid derivatives formation.
FR 1.437.361, publicada el 6 de Mayo de 1996, y la Patente de EE.UU. Nº 3.135.744, expedida el 2 de Junio de 1964, describen los éteres 17-(2-metil-2-butenílicos) y cicloalquenílicos de 5\alpha-androstano-3\alpha,17\beta-diol y 3-ésteres alcanoílicos inferiores del mismo. Se muestra que los compuestos tienen actividad androgénica y/o anabólica.FR 1,437,361, published May 6, 1996, and U.S. Patent No. 3,135,744, issued June 2, 1964, describe the ethers 17- (2-methyl-2-butenyl) and cycloalkenyl of 5α-androstane-3α, 17β-diol and 3-lower alkanoyl esters thereof. It shows that Compounds have androgenic and / or anabolic activity.
La Patente de EE.UU. Nº 4.197.296 de Phillips y otros, expedida el 8 de Abril de 1980, describe esteroides de la serie del androstano que poseen un grupo hidroxi en 3\alpha, un átomo de hidrógeno en 5\alpha o 5\beta y un grupo amino substituido en 11\alpha en donde la posición 17 puede no estar substituida. Se describe el compuesto 11\alpha-N,N-dimetilamino-2\beta-etoxi-5\alpha-androstan-3\alpha-ol. La patente describe que estos compuestos tienen actividad anestésica.U.S. Pat. No. 4,197,296 to Phillips and others, issued on April 8, 1980, describes steroids from the Androstane series that possess a 3α hydroxy group, a hydrogen atom in 5α or 5β and an amino group substituted in 11? where position 17 may not be replaced. The compound is described. 11α-N, N-dimethylamino-2β-ethoxy-5α-androstan-3α-ol. The patent describes that these compounds have activity anesthetic
La Patente de EE.UU. Nº 3.882.151 de Phillips y otros, expedida el 6 de Mayo de 1975, y la Patente de EE.UU. Nº 3.969.345 de Phillips y otros, expedida el 13 de Julio de 1976, describen 21-éteres de pregnano oxigenados en 3\alpha que poseen un grupo hidroxi en 3\alpha o un éster del mismo, un grupo ceto en la posición 20 y un grupo hidroxilo eterificado en la posición 21. El substituyente 21-éter es preferiblemente un grupo alcoxi, cicloalcoxi, aralcoxi o ariloxi que puede tener substituyentes adicionales. Las patentes describen que estos compuestos tienen actividad anestésica.U.S. Pat. No. 3,882,151 to Phillips and others, issued on May 6, 1975, and US Pat. No. 3,969,345 to Phillips et al., Issued July 13, 1976, describe 21-oxygenated 3α pregnan ethers possessing a 3α hydroxy group or an ester thereof, a keto group in position 20 and an etherified hydroxyl group at position 21. The 21-ether substituent is preferably an alkoxy group, cycloalkoxy, aralkoxy or aryloxy which may have substituents additional. Patents describe that these compounds have anesthetic activity
La Patente de EE.UU. Nº 3.959.260 de Phillips y otros, expedida el 25 de Mayo de 1976, describe anestésicos esteroideos de las series del pregnano y el 19-norpregnano que poseen un grupo hidroxi en 3\alpha, un grupo oxo en 20 y en la posición 21 el residuo de un nucleófilo que contiene azufre o un agrupamiento sulfona o sulfóxido. El substituyente en 3\beta puede ser hidrógeno o alquilo.U.S. Pat. No. 3,959,260 to Phillips and others, issued on May 25, 1976, describes anesthetics steroids of the pregnan series and the 19-norpregnano that possess a hydroxy group in 3α, an oxo group at 20 and at position 21 the residue of a nucleophile containing sulfur or a sulfone cluster or sulfoxide The 3β substituent can be hydrogen or I rent.
La Patente de EE.UU. Nº 3.822.298 de Clayton y otros, expedida el 2 de Julio de 1974, describe un procedimiento para preparar 3\alpha-hidroxi-5\alpha-esteroides. La patente describe la preparación de 21-benciloxi-3\alpha-hidroxi-5\alpha-pregnano-11,20-diona.U.S. Pat. No. 3,822,298 to Clayton and others, issued on July 2, 1974, describes a procedure to prepare 3α-hydroxy-5α-steroids. The patent describes the preparation of 21-benzyloxy-3α-hydroxy-5α-pregnano-11,20-dione.
La presente invención se dirige a nuevos derivados esteroideos de las series del androstano y el pregnano, así como a composiciones farmacéuticas y métodos para modular la excitabilidad cerebral. Más particularmente, la invención se refiere a derivados de 3\alpha-hidroxi, 17-éter de la serie del androstano. Estos derivados son capaces de actuar como un sitio recientemente identificado sobre el GRC, modulando de ese modo la excitabilidad cerebral de una manera que alivia el estrés, la ansiedad, el insomnio, los trastornos del estado de ánimo que son susceptibles de agentes activos para el GRC (tales como la depresión) y la actividad convulsiva.The present invention is directed to new Steroid derivatives of the Androstane and Pregnan series, as well as pharmaceutical compositions and methods to modulate the brain excitability. More particularly, the invention relates to 3α-hydroxy, 17-ether derivatives of the Androstane series. These derivatives are capable of acting as a recently identified site on the GRC, modulating from that brain excitability mode in a way that relieves stress, anxiety, insomnia, mood disorders that are susceptible of active agents for the GRC (such as depression) and seizure activity.
Se cree que el hidroxilo en 3\alpha también puede enmascararse como un éster farmacéuticamente aceptable debido al hecho de que el éster se disociará a medida que el profármaco se convierte en la forma de fármaco. Estos se denominan aquí ésteres disociables.It is believed that hydroxy in 3α also can be masked as a pharmaceutically acceptable ester because to the fact that the ester will dissociate as the prodrug It becomes the drug form. These are called esters here. dissociable
Los compuestos de la presente invención son moduladores de la excitabilidad del sistema nervioso central que están mediados por su capacidad para regular canales de iones cloruro asociados con el complejo receptor de GABA. Los experimentos de los solicitantes han establecido que estos compuestos tienen actividad anticonvulsiva, ansiolítica e hipnótica sedante similar a las acciones de agentes conocidos tales como las BZs, pero actúan en un sitio distinto sobre el GRC.The compounds of the present invention are central nervous system excitability modulators that they are mediated for their ability to regulate ion channels chloride associated with the GABA receptor complex. The applicants experiments have established that these Compounds have anticonvulsant, anxiolytic and hypnotic activity sedative similar to the actions of known agents such as BZs, but they act in a different place on the GRC.
La relación de metabolitos endógenos de progesterona con procesos asociados con la reproducción (ciclo de celo y preñez) está bien establecida (Marker, R.E. y otros, J. Am. Chem. Soc. 59:616-618 (1937)). Sin embargo, se acaba de conocer recientemente cómo tratar trastornos modulando la excitabilidad cerebral a través del uso de metabolitos esteroideos y sus derivados. Véanse la Patente de EE.UU. Nº 5.208.227, expedida el 4 de Mayo de 1993; la Patente de EE.UU. Nº 5.120.723, expedida el 9 de Junio de 1992, y la Patente de EE.UU. Nº 5.232.917, expedida el 3 de Agosto de 1993.The relationship of endogenous progesterone metabolites with processes associated with reproduction (heat cycle and pregnancy) is well established (Marker, RE et al., J. Am. Chem. Soc. 59 : 616-618 (1937)). However, it has just been recently known how to treat disorders by modulating brain excitability through the use of steroid metabolites and their derivatives. See US Pat. No. 5,208,227, issued May 4, 1993; U.S. Patent No. 5,120,723, issued June 9, 1992, and US Pat. No. 5,232,917, issued on August 3, 1993.
Objetivos deseables de las composiciones farmacéuticas y los métodos de esta invención son el tratamiento del estrés, la ansiedad, PMS, PND y ataques tales como los provocadas por la epilepsia, para mejorar o evitar las crisis de ansiedad, la tensión muscular y la depresión común en pacientes que sufren estas anormalidades del sistema nervioso central. Un objetivo deseable adicional de las composiciones y los métodos es tratar el insomnio y producir actividad hipnótica. Otro objetivo deseable de los compuestos y los métodos es inducir la anestesia, particularmente mediante administración intravenosa. La presente invención se dirige a nuevos compuestos y su uso en composiciones farmacéuticas y métodos para tratar tales trastornos modulando la excitabilidad cerebral.Desirable objectives of the compositions Pharmaceuticals and the methods of this invention are the treatment of stress, anxiety, PMS, PND and attacks such as caused by epilepsy, to improve or prevent seizures of anxiety, muscle tension and common depression in patients who suffer these abnormalities of the central nervous system. A Additional desirable objective of the compositions and methods is Treat insomnia and produce hypnotic activity. Other objective desirable of the compounds and methods is to induce anesthesia, particularly by intravenous administration. The present invention is directed to new compounds and their use in compositions pharmaceuticals and methods to treat such disorders by modulating the brain excitability.
Otro aspecto de la presente invención se refiere a un método para inducir el sueño y mantener substancialmente el nivel de sueño REM que se encuentra en el sueño normal, en donde no se induce un insomnio de rebote substancial, según se define aquí. Este método comprende administrar una cantidad eficaz de un compuesto de la invención. Los compuestos de la invención son capaces de incrementar el sueño REM y el período de sueño total, sin afectar substancialmente a la cantidad de sueño REM.Another aspect of the present invention relates to to a method to induce sleep and substantially maintain the REM sleep level found in normal sleep, where not substantial rebound insomnia is induced, as defined herein. This method comprises administering an effective amount of a compound of the invention. The compounds of the invention are capable of increasing REM sleep and the period of total sleep, without substantially affecting the amount of REM sleep.
La presente invención puede entenderse mejor y sus ventajas apreciarse haciendo referencia al dibujo adjunto, en el que:The present invention can be better understood and Its advantages can be appreciated by referring to the attached drawing, in the one who:
la figura 1 es una gráfica del transcurso del tiempo de la actividad anti-metrazólica de un profármaco de 3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano (administrado i.p. a una dosis de 20,0 mg/kg).Figure 1 is a graph of the course of the time of the anti-metrazole activity of a prodrug of 3α-hydroxy-17β-methoxy-5α-androstane (administered i.p. at a dose of 20.0 mg / kg).
Estudios previos (Gee, K.W. y otros, European Journal of Pharmacology, 136:419-423 (1987)) demostraron que ciertos esteroides hidroxilados en 3\alpha son órdenes de magnitud más potentes como moduladores del GRC de lo que otros habían presentado (Majewska, M.D. y otros, Science 232:1004-1007 (1986); Harrison, N.L. y otros, J. Pharmacol. Exp. Ther. 241:346-353 (1987)). Majewska y otros y Harrison y otros mostraron que los esteroides reducidos en 5 hidroxilados en 3\alpha solo son capaces de niveles de eficacia mucho menores. Los datos experimentales in vitro e in vivo han demostrado que la alta potencia de estos esteroides los permite ser terapéuticamente útiles en la modulación de la excitabilidad cerebral a través del GRC (Gee, K.W. y otros, European Journal of Pharmacology, 136:419-423 (1987); Wieland y otros, Psychopharmacology 118(1):65-71 (1995)). Diversos esteroides sintéticos se han preparado como esteroides neuroactivos. Véase, por ejemplo, la Patente de EE.UU. Nº 5.232.917, expedida el 3 de Agosto de 1993, que describe compuestos esteroideos neuroactivos útiles para tratar el estrés, la ansiedad, el insomnio, trastornos convulsivos y trastornos del estado de ánimo que son susceptibles de agentes activos para el GRC, tales como depresión, de una manera terapéuticamente beneficiosa. Por otra parte, se ha demostrado previamente que estos esteroides interactúan en un sitio único sobre el GRC que es distinto de otros sitios de interacción conocidos (es decir, barbiturato, BZ y GABA) donde se han producido previamente efectos beneficiosos terapéuticos sobre el estrés, la ansiedad, el sueño, trastornos del estado de ánimo y trastornos convulsivos (Gee, K.W. y Yamamura, H.I., "Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety, Insomnia and Seizure Disorders", en Central Nervous System Disorders, D.C. Horvell, ed., Marcel-Dekker, Nueva York (1985), pp. 123-147; Lloyd, K.G. y Morselli, P.L., "Psychopharmacology of GABAergic Drugs", en Psychoparhamacology: The Third Generation of Progress, H.Y. Meltzer, ed., Raven Press, N.Y. (1987), pp. 183-195; y Gee, K.W. y otros, European Journal of Pharmacology, 136:419-423 (1987). Estos compuestos son deseables por su duración, potencia y actividad oral (junto con otras formas de administración).Previous studies (Gee, KW and others, European Journal of Pharmacology, 136 : 419-423 (1987)) showed that certain 3α hydroxylated steroids are orders of magnitude more potent as GRC modulators than others had presented (Majewska , MD et al., Science 232 : 1004-1007 (1986); Harrison, NL et al., J. Pharmacol. Exp. Ther. 241 : 346-353 (1987)). Majewska et al. And Harrison et al. Showed that steroids reduced by 5 hydroxylates at 3? Are only capable of much lower levels of efficacy. In vitro and in vivo experimental data have shown that the high potency of these steroids allows them to be therapeutically useful in modulating brain excitability through the GRC (Gee, KW et al., European Journal of Pharmacology, 136 : 419-423 (1987); Wieland et al., Psychopharmacology 118 (1): 65-71 (1995)). Various synthetic steroids have been prepared as neuroactive steroids. See, for example, US Pat. No. 5,232,917, issued on August 3, 1993, which describes neuroactive steroidal compounds useful for treating stress, anxiety, insomnia, seizure disorders and mood disorders that are susceptible to active agents for GRC, such as depression, in a therapeutically beneficial way. On the other hand, it has been previously shown that these steroids interact in a single site on the GRC that is distinct from other known interaction sites (i.e., barbiturate, BZ and GABA) where therapeutic beneficial effects on stress have previously occurred, anxiety, sleep, mood disorders and seizure disorders (Gee, KW and Yamamura, HI, "Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety, Insomnia and Seizure Disorders", in Central Nervous System Disorders , DC Horvell, ed., Marcel-Dekker, New York (1985), pp. 123-147; Lloyd, KG and Morselli, PL, "Psychopharmacology of GABAergic Drugs", in Psychoparhamacology: The Third Generation of Progress , HY Meltzer, ed., Raven Press, NY (1987), pp. 183-195; and Gee, KW et al., European Journal of Pharmacology, 136 : 419-423 (1987) These compounds are desirable for their duration, potency and oral activity (along with others forms of administration).
De acuerdo con la presente invención y según se usa aquí, los siguientes términos, cuando aparecen solos o como parte de un resto, se definen con el siguiente significado, a no ser que se indique explícitamente otra cosa.In accordance with the present invention and according to use the following terms here, when they appear alone or as part of a remainder, are defined with the following meaning, not unless explicitly stated otherwise.
El término "alquilo", según se usa aquí en todos los casos, se refiere a grupos alifáticos saturados incluyendo grupos de cadena lineal, cadena ramificada y cíclicos, todos los cuales pueden estar opcionalmente substituidos. Grupos alquilo preferidos contienen de 1 a 10 átomos de carbono. Grupos alquilo adecuados incluyen metilo, etilo y similares, y pueden estar opcionalmente substituidos.The term "alkyl," as used herein in All cases, refers to saturated aliphatic groups including linear, branched and cyclic chain groups, all of which may be optionally substituted. Groups Preferred alkyl contain from 1 to 10 carbon atoms. Groups Suitable alkyl include methyl, ethyl and the like, and may be optionally substituted.
El término "alquenilo", según se usa aquí en todos los casos, se refiere a grupos insaturados que contienen al menos un doble enlace carbono-carbono e incluye grupos de cadena lineal, cadena ramificada y cíclicos, todos los cuales pueden estar opcionalmente substituidos. Grupos alquenilo preferibles tienen de 2 a 10 átomos de carbono.The term "alkenyl," as used herein in all cases, refers to unsaturated groups that contain the minus a carbon-carbon double bond and includes linear, branched and cyclic chain groups, all which may be optionally substituted. Alkenyl groups Preferable have 2 to 10 carbon atoms.
El término "alquinilo", según se usa aquí en todos los casos, se refiere a grupos hidrocarbúricos insaturados que contienen al menos un triple enlace carbono-carbono e incluye grupos de cadena lineal y cadena ramificada que pueden estar opcionalmente substituidos. Grupos alquinilo preferidos tienen de dos a ocho átomos de carbono. Grupos alquinilo más preferidos tienen de dos a doce átomos de carbono. Los grupos alquinilo más preferidos tienen de dos a siete átomos de carbono. Grupos alquinilo adecuados incluyen etinilo, propinilo, butinilo, pentinilo y similares, que pueden estar opcionalmente substituidos con ciano, acetoxi, halo, hidroxi o ceto.The term "alkynyl," as used herein in all cases, refers to unsaturated hydrocarbon groups that contain at least one triple link carbon-carbon and includes linear chain groups and branched chain that may be optionally substituted. Preferred alkynyl groups have two to eight carbon atoms. Most preferred alkynyl groups have two to twelve atoms of carbon. The most preferred alkynyl groups have two to seven carbon atoms Suitable alkynyl groups include ethynyl, propynyl, butynyl, pentinyl and the like, which may be optionally substituted with cyano, acetoxy, halo, hydroxy or keto
El término "alcoxi" se refiere al éter-O-alquilo, en donde alquilo se define como previamente.The term "alkoxy" refers to the ether-O-alkyl, where alkyl is Define as previously.
El término "ariloxi" se refiere al éter-O-arilo, en el que el arilo se define aquí más adelante.The term "aryloxy" refers to the ether-O-aryl, in which the aryl is define here later.
El término "arilo" se refiere a grupos aromáticos que tienen al menos un anillo que tiene un sistema de electrones pi conjugados e incluye arilo carbocíclico y biarilo, ambos de los cuales pueden estar opcionalmente substituidos. Grupos arilo preferidos tienen de 6 a 10 átomos de carbono. Grupos arilo adecuados incluyen fenilo y naftilo.The term "aryl" refers to groups aromatics that have at least one ring that has a system of conjugated pi electrons and includes carbocyclic aryl and biaryl, both of which may be optionally substituted. Groups Preferred aryl have 6 to 10 carbon atoms. Arilo groups Suitable include phenyl and naphthyl.
El término "arilo carbocíclico" se refiere a grupos en los que los átomos de anillo en el anillo aromático son átomos de carbono. Grupos arilo carbocíclico incluyen grupos fenilo y naftilo, grupos que están opcionalmente substituidos. El fenilo substituido tiene preferiblemente de uno a tres, cuatro o cinco substituyentes, siendo estos ventajosamente alquilo inferior, amino, aminocarbonilo, ciano, éster de carboxilato, hidroxi, alcoxi inferior, halógeno, acilo inferior y nitro.The term "carbocyclic aryl" refers to groups in which the ring atoms in the aromatic ring are carbon atoms Carbocyclic aryl groups include phenyl groups and naphthyl, groups that are optionally substituted. Phenyl substituted has preferably one to three, four or five substituents, these being advantageously lower alkyl, amino, aminocarbonyl, cyano, carboxylate ester, hydroxy, alkoxy lower, halogen, lower acyl and nitro.
El término "aralquilo" se refiere a un grupo alquilo substituido con un grupo arilo. Grupos aralquilo adecuados incluyen bencilo y similares, y pueden estar opcionalmente substituidos.The term "aralkyl" refers to a group alkyl substituted with an aryl group. Suitable aralkyl groups include benzyl and the like, and may optionally be replaced.
El término "alcanoiloxi" se refiere a -O-C(O)R^{a}, en donde R^{a} es alquilo, alquenilo, alquinilo, arilo o aralquilo.The term "alkanoyloxy" refers to -O-C (O) R a, where R a is alkyl, alkenyl, alkynyl, aryl or aralkyl.
El término "carbalcoxi" se refiere a -C(O)OR^{b}, en donde R^{b} es alquilo, alquenilo, alquinilo arilo o aralquilo.The term "carbalkoxy" refers to -C (O) OR b, wherein R b is alkyl, alkenyl, alkynyl aryl or aralkyl.
El término "carboxamido" se refiere a -C(O)NR^{c}R^{d}, en donde R^{c} y R^{d} se seleccionan independientemente de hidrógeno, alquilo, alquenilo, alquinilo, arilo o aralquilo.The term "carboxamido" refers to -C (O) NR c R d, wherein R c and R d are independently select hydrogen, alkyl, alkenyl, alkynyl, aryl or aralkyl.
El término "acilo" se refiere al grupo alcanoílo -C(O)R^{g}, donde R^{g} es alquilo, alquenilo, alquinilo, arilo o aralquilo.The term "acyl" refers to the group alkanoyl -C (O) R g, where R g is alkyl, alkenyl, alkynyl, aryl or aralkyl.
El término "amino" se refiere a -NR^{h}R^{i}, donde R^{h} y R^{i} son independientemente hidrógeno o alquilo inferior o están conectados entre sí (con el átomo de nitrógeno al que están unidos) para dar un anillo de 5 ó 6 miembros, por ejemplo anillos de pirrolidina, morfolino o piperidina. El término "dialquilamino" se refiere a -NR^{e}R^{f}, donde R^{e} y R^{f} son independientemente grupos alquilo inferior o junto con el átomo de carbono al que están unidos forman el resto de un grupo morfolino. Grupos dialquilamino adecuados incluyen dimetilamino, dietilamino y morfolino.The term "amino" refers to -NR h R i, where R h and R i are independently hydrogen or lower alkyl or are connected to each other (with the nitrogen atom to which they are attached) to give a ring of 5 or 6 members, for example pyrrolidine, morpholino or rings piperidine The term "dialkylamino" refers to -NR e R f, where R e and R f are independently lower alkyl groups or together with the carbon atom to which they are joined form the rest of a morpholino group. Groups Suitable dialkylamino include dimethylamino, diethylamino and morpholino
El término "tio" se refiere a -SR^{m}, donde R^{m} es hidrógeno, alquilo, alquenilo, alquinilo, arilo o aril-alquilo(inferior).The term "uncle" refers to -SRm, where R m is hydrogen, alkyl, alkenyl, alkynyl, aryl or aryl-alkyl (lower).
El término "sulfinilo" se refiere a -SOR^{n}, donde R^{n} es alquilo, alquenilo, alquinilo, arilo o aril-alquilo(inferior).The term "sulfinyl" refers to -SOR n, where R n is alkyl, alkenyl, alkynyl, aryl or aryl-alkyl (lower).
El término "sulfonilo" se refiere a -SO_{2}Rº, donde Rº es hidrógeno, alquilo, alquenilo, alquinilo, arilo o aril-alquilo(inferior).The term "sulfonyl" refers to -SO2Rº, where Rº is hydrogen, alkyl, alkenyl, alkynyl, aryl or aryl-alkyl (lower).
El término "sulfonamido" se refiere a -SO_{2}NR^{k}R^{l}, en donde R^{k} y R^{l} son independientemente hidrógeno o alquilo inferior.The term "sulfonamido" refers to -SO 2 NR k R l, wherein R k and R l are independently hydrogen or lower alkyl.
El término "opcionalmente substituido" o "substituido", a no ser que se defina aquí específicamente otra cosa, se refiere a grupos substituidos por de uno a cinco substituyentes, seleccionados independientemente de alquilo inferior (acíclico y cíclico), arilo (carboarilo y heteroarilo), alquenilo, alquinilo, alcoxi, halo, haloalquilo (incluyendo trihaloalquilo, por ejemplo trifluorometilo), amino, mercapto, alquiltio, alquilsulfinilo, alquilsulfonilo, nitro, alcanoílo, alcanoiloxi, alcanoiloxialcanoílo, alcoxicarboxi, carbalcoxi (-COOR^{j}, en donde R^{j} es alquilo inferior), carboxamido (-CONR^{k}R^{l}, en donde R^{k} y R^{l} se definen como previamente), formilo, carboxi, hidroxi, ciano, azido, alcanoilamido, heteroariloxi, heterocarbociclooxi y sales de éster de hemisuccinato.The term "optionally substituted" or "substituted", unless specifically defined here otherwise, it refers to groups substituted by one to five substituents, independently selected from lower alkyl (acyclic and cyclic), aryl (carboaryl and heteroaryl), alkenyl, alkynyl, alkoxy, halo, haloalkyl (including trihaloalkyl, for example trifluoromethyl), amino, mercapto, alkylthio, alkylsulfinyl, alkylsulfonyl, nitro, alkanoyl, alkanoyloxy, alkanoyloxyalkanoyl, alkoxycarboxy, carbalkoxy (-COOR j, in where R j is lower alkyl), carboxamido (-CONR k R l, where R k and R l are defined as previously), formyl, carboxy, hydroxy, cyano, azido, alkanoylamido, heteroaryloxy, heterocarbocyclooxy and ester salts of hemisuccinate.
El término "inferior" se menciona aquí en relación con radicales orgánicos o compuestos y define desde uno hasta e incluyendo diez, preferiblemente hasta e incluyendo seis, y ventajosamente de uno a cuatro átomos de carbono. Tales grupos pueden ser de cadena lineal, de cadena ramificada o cíclicos.The term "inferior" is mentioned here in relationship with organic radicals or compounds and defined from one up to and including ten, preferably up to and including six, and advantageously from one to four carbon atoms. Such groups they can be straight chain, branched chain or cyclic.
El término "heterocíclico" se refiere a radicales que contienen carbonos que tienen anillos de tres, cuatro, cinco, seis o siete miembros y uno o dos heteroátomos O, N o S, por ejemplo tiazolidina, tetrahidrofurano, 1,4-dioxano, 1,3,5-trioxano, pirrolidina, piperidina, quinuclidina, ditiano, tetrahidropirano, \varepsilon-caprolactona, \varepsilon-caprolactama, \omega-tiocaprolactama y morfolina.The term "heterocyclic" refers to carbon-containing radicals that have rings of three, four, five, six or seven members and one or two heteroatoms O, N or S, for example thiazolidine, tetrahydrofuran, 1,4-dioxane, 1,3,5-trioxane, pyrrolidine, piperidine, quinuclidine, dithian, tetrahydropyran, ε-caprolactone, ε-caprolactam, ome-thiocaprolactam and morpholine.
El término "heteroarilo" se refiere a radicales insaturados cíclicos de 5-14 miembros que contienen carbono, que contienen uno, dos, tres o cuatro átomos de O, N o S y que tienen 6, 10 ó 14 electrones \pi deslocalizados en uno o más anillos, por ejemplo piridina, oxazol, indol, purina, pirimidina, imidazol, bencimidazol, indazol, 2H-1,2,4-triazol, 1,2,3-triazol, 2H-1,2,3,4-tetrazol, 1H-1,2,3,4-tetrazol, benzotriazol, 1,2,3-triazolo[4,5-\beta]piridina, tiazol, isoxazol, pirazol, quinolina, citosina, timina, uracilo, adenina, guanina, pirazina, ácido picolínico, picolina, ácido furoico, furfural, alcohol furílico, carbazol, 9H-pirido[3,4-\beta]indol, isoquinolina, pirrol, tiofeno, furano, 9(10H)-acridona, fenoxazina y fenotiazina, cada uno de los cuales puede estar opcionalmente substituido según se analiza previamente.The term "heteroaryl" refers to 5-14 cyclic unsaturated radicals that they contain carbon, which contain one, two, three or four atoms of O, N or S and that have 6, 10 or 14 electrons \ pi delocalized in one or more rings, for example pyridine, oxazole, indole, purine, pyrimidine, imidazole, benzimidazole, indazole, 2H-1,2,4-triazole, 1,2,3-triazole, 2H-1,2,3,4-tetrazole, 1H-1,2,3,4-tetrazole, benzotriazole, 1,2,3-triazolo [4,5- [beta]] pyridine, thiazole, isoxazole, pyrazole, quinoline, cytosine, thymine, uracil, adenine, guanine, pyrazine, picolinic acid, picoline, acid furoic, furfural, furyl alcohol, carbazole, 9H-pyrido [3,4-?] Indole, isoquinoline, pyrrole, thiophene, furan, 9 (10H) -acridone, phenoxazine and phenothiazine, each of which may be optionally substituted according to It is previously analyzed.
El término "sal de amonio cuaternario" se refiere a sales de amonio cuaternario de compuestos amínicos y compuestos heteroarílicos descritos previamente, formadas mediante la reacción del compuesto amínico o el compuesto heteroarílico con un reactivo electrófilo tal como un haluro, tosilato, sulfato, mesilato o similares de alquilo, alquenilo, alquinilo, cicloalquilalquilo, aralquilo o aralquinilo. Ejemplos específicos de reactivos electrófilos incluyen yoduro de metilo, yoduro de etilo, yoduro de n-butilo y yoduro de fenetilo.The term "quaternary ammonium salt" is refers to quaternary ammonium salts of amine compounds and heteroaryl compounds described previously, formed by the reaction of the amino compound or the heteroaryl compound with an electrophilic reagent such as a halide, tosylate, sulfate, mesylate or the like of alkyl, alkenyl, alkynyl, cycloalkylalkyl, aralkyl or aralkynyl. Specific examples of electrophilic reagents include methyl iodide, iodide ethyl, n-butyl iodide and phenethyl iodide.
El término "EDA" se refiere a etilendiamina.The term "EDA" refers to ethylenediamine
El término "ésteres o sales farmacéuticamente aceptables" se refiere a ésteres o sales de Fórmula I derivados de la combinación de un compuesto de esta invención y un ácido o una base orgánicos o inorgánicos. Las sales básicas se forman mezclando una solución de un compuesto particular de la presente invención con una solución de una base atóxica farmacéuticamente aceptable, tal como hidróxido sódico, hidróxido potásico, bicarbonato sódico, carbonato sódico o un compuesto amínico, tal como hidróxido de colina, Tris, bis-Tris, N-metilglucamina, arginina y similares. Las sales ácidas se forman mezclando una solución de un compuesto particular de la presente invención con una solución de un ácido orgánico o ácido dioico atóxico farmacéuticamente aceptable, tal como acético, propiónico, maleico, fumárico, ascórbico, pimélico, succínico, glutárico, bismetilensalicílico, metanosulfónico, etanodisulfónico, oxálico, tartárico, salicílico, cítrico, glucónico, itacónico, glicólico, p-aminobenzoico, aspártico, glutámico, gamma-aminobutírico, \alpha-(2-hidroxietilamino)propiónico, glicina y otros \alpha-aminoácidos, fosfórico, sulfúrico, glucurónico y 1-metil-1,4-dihidronicotínico. Los ésteres se forman a partir de alcoholes esteroideos y un ácido adecuadamente activado. Los ésteres se analizan adicionalmente aquí.The term "pharmaceutically esters or salts Acceptable "refers to esters or salts of Formula I derived of the combination of a compound of this invention and an acid or an organic or inorganic base. The basic salts are formed mixing a solution of a particular compound of the present invention with a solution of a pharmaceutically non-toxic base acceptable, such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate or an amino compound, such as choline hydroxide, Tris, bis-Tris, N-methylglucamine, arginine and the like. Salts acids are formed by mixing a solution of a particular compound of the present invention with a solution of an organic acid or pharmaceutically acceptable non-toxic dioic acid, such as acetic acid, propionic, maleic, fumaric, ascorbic, pimelic, succinic, glutaric, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, oxalic, tartaric, salicylic, citric, gluconic, itaconic, glycolic, p-aminobenzoic, aspartic, glutamic, gamma-aminobutyric acid, α- (2-hydroxyethylamino) propionic, glycine and other α-amino acids, phosphoric, sulfuric, glucuronic and 1-methyl-1,4-dihydronicotinic. Esters are formed from steroidal alcohols and an acid properly activated. The esters are further analyzed here.
El término "ácidos dioicos" se refiere a grupos alquileno de 1 a 5 átomos de carbono substituidos con dos grupos carboxi, por ejemplo ácido malónico, ácido succínico, ácido glutárico, ácido adípico, ácido pimélico y ácido subérico. Sales de hemi-éster de los ácidos dioicos incluyen las sales de sodio, litio, potasio, magnesio y calcio de los mismos.The term "dioic acids" refers to alkylene groups of 1 to 5 carbon atoms substituted with two carboxy groups, for example malonic acid, succinic acid, acid glutaric acid, adipic acid, pimelic acid and suberic acid. You leave Hemi-ester of dioic acids include sodium, lithium, salts potassium, magnesium and calcium thereof.
De acuerdo con la presente invención, cetales incluyen diéteres de alcanoles inferiores, por ejemplo dimetil- y dietil-cetales, así como cetales cíclicos que incluyen diéteres de alcanodioles de 2-3 átomos de carbono, que pueden estar opcionalmente substituidos, por ejemplo etilencetales y propilencetales.According to the present invention, ketals include diesters of lower alkanols, for example dimethyl- and diethyl-ketals, as well as cyclic ketals that they include alkanediyl diesters of 2-3 atoms of carbon, which may be optionally substituted, for example ethylencetals and propylencetals.
En sus aspectos más amplios, la presente invención se dirige a derivados esteroideos que tienen la fórmula general I:In its broadest aspects, this invention is directed to steroid derivatives having the formula general I:
o un 3-éster farmacéuticamente aceptable de los mismos; en dondeor a pharmaceutically 3-ester acceptable thereof; in where
R es uno de hidrógeno, amino, tio, sulfinilo, sulfonilo, halógeno, alcoxi de 1 a 10 átomos de carbono, alquilo substituido, alquenilo o alquinilo substituido;R is one of hydrogen, amino, thio, sulfinyl, sulfonyl, halogen, alkoxy of 1 to 10 carbon atoms, alkyl substituted, alkenyl or substituted alkynyl;
R_{1} es uno de hidrógeno, alquilo, alquenilo, alquinilo, haloalquilo, dihaloalquilo, trihaloalquilo, aralquinilo opcionalmente substituido, alcoxialquilo, aminoalquilo, ciano, cianoalquilo, tiocianoalquilo, azidoalquilo, arilalquilo opcionalmente substituido, arialquenilo, arilo opcionalmente substituido, aralquilalquinilo opcionalmente substituido, alcanoiloxialquinilo, heteroariloxialquinilo opcionalmente substituido, oxoalquinilo o un cetal del mismo, cianoalquinilo, heteroarilalquinilo opcionalmente substituido, hidroxialquinilo, alcoxialquinilo, aminoalquinilo, acilaminoalquinilo, mercaptoalquinilo, hidroxialquinilo, hemi-éster de ácido dioico o una sal del mismo o alquiniloxialquinilo;R1 is one of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, dihaloalkyl, trihaloalkyl, aralkynyl optionally substituted, alkoxyalkyl, aminoalkyl, cyano, cyanoalkyl, thiocyanoalkyl, azidoalkyl, arylalkyl optionally substituted, arialkenyl, aryl optionally substituted, optionally substituted aralkylalkyl, alkanoyloxyalkynyl, heteroaryloxyalkynyl optionally substituted, oxoalkynyl or a ketal thereof, cyanoalkynyl, optionally substituted heteroarylalkyl, hydroxyalkynyl, alkoxyalkynyl, aminoalkynyl, acylaminoalkynyl, mercaptoalkynyl, hydroxyalkynyl, hemi-ester of dioic acid or a salt thereof or alkynyloxyalkynyl;
R_{2} es uno de hidrógeno, alcoxi, un grupo ceto o un grupo dimetilamino;R2 is one of hydrogen, alkoxy, a group keto or a dimethylamino group;
R_{3} es uno de alcoxi opcionalmente substituido, alqueniloxi, alquiniloxi, ariloxi opcionalmente substituido o arilalcoxi opcionalmente substituido;R 3 is optionally one of alkoxy substituted, alkenyloxy, alkynyloxy, aryloxy optionally substituted or optionally substituted arylalkoxy;
R_{4} es uno de hidrógeno o metilo;R 4 is one of hydrogen or methyl;
R_{5}, R_{6}, R_{7}, R_{8}, R_{9} y R_{10} son cada uno hidrógeno;R 5, R 6, R 7, R 8, R 9 and R 10 are each hydrogen;
y las líneas punteadas representan todas enlaces sencillos;and the dotted lines represent all links simple;
con tal de que:provided that:
cuando R_{3} sea alcoxi de 1 a 6 átomos de carbono o alcoxi de 1 a 6 átomos de carbono substituido o alqueniloxi de 1 a 6 átomos de carbono y R sea hidrógeno o \alpha-metilo, entonces R_{1} sea distinto de hidrógeno;when R 3 is alkoxy of 1 to 6 atoms of carbon or alkoxy of 1 to 6 substituted carbon atoms or alkenyloxy of 1 to 6 carbon atoms and R be hydrogen or α-methyl, then R1 is different from hydrogen;
y cuando R_{3} sea alcoxi(de 1 a 4 átomos de carbono)-alcoxi(de 1 a 4 átomos de carbono), entonces R_{1} sea distinto de hidrógeno o 1-propinilo;and when R 3 is alkoxy (from 1 to 4 carbon atoms) -alkoxy (from 1 to 4 atoms of carbon), then R1 is other than hydrogen or 1-propynyl;
definiéndose previamente el término "substituido" u "opcionalmente substituido".previously defining the term "substituted" or "optionally substituted".
La presente invención también incluye ésteres y sales farmacéuticamente aceptables de los compuestos de Fórmula I, incluyendo sales de adición de ácidos. Se cree que el 3\alpha-hidroxilo también puede estar enmascarado como un éster farmacéuticamente aceptable debido al hecho de que el éster se disociará como el profármaco y se convierte en la forma de fármaco. Estos se denominan aquí ésteres disociables.The present invention also includes esters and pharmaceutically acceptable salts of the compounds of Formula I, including acid addition salts. It is believed that the 3α-hydroxyl may also be masked as a pharmaceutically acceptable ester due to the fact that the ester will dissociate as the prodrug and becomes the form of drug. These are referred to herein as dissociable esters.
Cada uno de los siguientes grupos de valores preferidos se aplica a todas las modalidades de la presente invención, a no ser que se estipule otra cosa específicamente. Compuestos preferidos de Fórmula I incluyen compuestos en los que R es hidrógeno o alcoxi inferior, prefiriéndose más el hidrógeno; R_{3} se define como previamente y es preferiblemente uno de los grupos descritos más adelante aquí; y R_{1} es arilalquinilo substituido, por ejemplo R_{1} es fenilalquinilo substituido en 4, tal como 4-acetilfenilalquinilo, 4-metoxifeniletinilo, 4-N,N-dimetilaminofeniletinilo, 4-cianofeniletinilo, éster etílico de 4-carboxifeniletinilo, 4-N-dialquilamidofeniletinilo, o en donde R_{1} es oxoalquinilo, hidroxialquinilo, acetoxialquinilo, cianoalquinilo o alcoxialquinilo.Each of the following groups of values Preferred applies to all modalities of this invention, unless otherwise specifically stipulated. Preferred compounds of Formula I include compounds in which R it is hydrogen or lower alkoxy, with hydrogen being more preferred; R 3 is defined as previously and is preferably one of the groups described later here; and R1 is arylalkyl substituted, for example R 1 is phenylalkyl substituted in 4, such as 4-acetylphenylalkyl, 4-methoxyphenylethynyl, 4-N, N-dimethylaminophenylethynyl, 4-cyanophenylethynyl, ethyl ester of 4-carboxyphenylethynyl, 4-N-dialkylamidophenylethynyl, or in where R 1 is oxoalkynyl, hydroxyalkynyl, acetoxyalkynyl, cyanoalkynyl or alkoxyalkynyl.
Compuestos preferidos adicionales son compuestos de Fórmula I en los que R es hidrógeno, halo, alcoxi inferior, alquinilo o alquinilo substituido; R_{1} es ariletinilo substituido; R_{2} es hidrógeno, un grupo ceto o un grupo dimetilamino; y R_{4} es hidrógeno o metilo.Additional preferred compounds are compounds of Formula I in which R is hydrogen, halo, lower alkoxy, alkynyl or substituted alkynyl; R1 is ariletinyl replaced; R2 is hydrogen, a keto group or a group dimethylamino; and R 4 is hydrogen or methyl.
Compuestos preferidos de la presente invención
incluyen:
3\alpha-hidroxi-3\beta-feniletinil-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-feniletinil-17\beta-metoxi-5\alpha-androstano;
3\alpha-hidroxi-3\beta-(3',4'-dimetoxifenil)etinil-17\beta-metoxi-5\beta-
androstano;
3\alpha-hidroxi-3\beta-(4'-metilfenil)etinil-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-(2'-metoxifenil)etinil-17\beta-metoxi-5\beta-androstano;
éster etílico de
3\alpha-hidroxi-3\beta-(4'-carboxifenil)etinil-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-(4'-acetoxiacetilfenil)etinil-17\beta-metoxi-5\beta-androstano;
3\beta-(4'-acetilfenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\alpha-an-
drostano;
3\beta-(4'-acetilfenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\beta-(4'-dimetilaminofenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\beta-(4'-bifenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-(4'-nitrofenil)etinil-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-(4'-metóxifenil)etinil-17\beta-metoxi-5\beta-androstano;
3\beta-(4'-trifluoro-
metilfenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\beta-(4'-clorofenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\beta-(4'-cianofenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\beta-(4'(R/S)-hidroxipentinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-fenil-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-bencil-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-(2'-feniletil)-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-[2-(3',4'-dimetoxifenil)etil]-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-[6'-oxo-1'-heptinil]-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-(7'-oxo-1'-octinil)-
17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-(4'-oxo-1'-pentinil)-17\beta-metoxi-5\beta-androstano;
3\beta-[5'-(R/S)-hidroxihexinil]-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\beta-(4'-hidroxibutinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\beta-(4'-hidroxibutinil)-3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano;
3\beta-(4'-acetoxifeniletinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\beta-(4'-acetilfeniletinil)-3\alpha-hidroxi-19-nor-17\beta-metoxi-5\beta-androstano;
éster etílico de
3\beta-(4'-carboxifeniletinil)-3\alpha-hidroxi-19-nor-17\beta-metoxi-5\beta-androstano;
éster etílico de
3\beta-(4'-carboxifeniletinil)-3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano;
3\beta-[4'-(N,N-dietilcarboxamido)fenil]etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-[5-oxo-1-hexinil]-17\beta-metoxi-5\beta-androstano;
5'-(1,2-etanodiilacetal) cíclico de
3\alpha-hidroxi-3\beta-[5'-oxo-1'-hexinil]-17\beta-metoxi-5\beta-androstano;
3\beta-(5-ciano-1-pentinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-(2-piridil)etinil-17\beta-
metoxi-5\beta-androstano;
3\beta-(6-hidroxi-1-hexinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
sal sódica de 6'-hemisuccinato de
3\beta-(6'-hidroxi-1'-hexinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\beta-(5'-hidroxi-1'-pentinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
sal sódica de 5'-hemisuccinato de
3\beta-(5'-hidroxi-1'-pentinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
sal sódica de 4'-hemisuccinato de
\beta-(4'-hidroxi-1'-butinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\beta-(4'-ciano-1'-butinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\beta-(5'-acetoxi-1'-pentinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-an-
drostano;
3\beta-(4'-acetoxi-1'-butinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\beta-(4'-acetoxi-1'-butinil)-3\alpha-hidroxi-
17\beta-metoxi-5\alpha-androstano;
3\beta-(6'-acetoxi-1'-hexinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-[3-(2'-propiniloxi)-1-propinil]-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-(3-metoxi-1-propinil)-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-(3-metoxi-1-propinil)-17\beta-metoxi-5\alpha-androstano;
3\alpha-hidroxi-3\beta-[3-(4'-piridiniloxi)-1-propinil]-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-[3-(1'H-1,2,3-triazol-1'-il)-1-propinil]-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-[3-(2'H-1,2,3-triazol-2'-il)-1-propinil]-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-(2'-tienil)etinil-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-(3'-fenil-1'-propinil)-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-(3'-fenilpropil)-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-[3-(1'H-pirazol-1'-il)-1-propinil]-17\beta-metoxi-5\beta-androstano;
3\beta-(3'-acetilfeniletinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano
y
3\beta-(3'-acetoxi-3'-propinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano.Preferred compounds of the present invention include: 3α-hydroxy-3β-phenylethynyl-17β-methoxy-5β-androstane; 3α-hydroxy-3β-phenylethynyl-17β-methoxy-5α-androstane; 3α-hydroxy-3β- (3 ', 4'-dimethoxyphenyl) ethynyl-17β-methoxy-5β-
androstane; 3α-hydroxy-3β- (4'-methylphenyl) ethynyl-17β-methoxy-5β-androstane; 3α-hydroxy-3β- (2'-methoxyphenyl) ethynyl-17β-methoxy-5β-androstane; 3α-hydroxy-3β- (4'-carboxyphenyl) ethynyl-17β-methoxy-5β-androstane ethyl ester; 3α-hydroxy-3β- (4'-acetoxyacetylphenyl) ethynyl-17β-methoxy-5β-androstane; 3β- (4'-acetylphenyl) ethynyl-3α-hydroxy-17β-methoxy-5α-an-
drostane; 3β- (4'-acetylphenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-dimethylaminophenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-biphenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3α-hydroxy-3β- (4'-nitrophenyl) ethynyl-17β-methoxy-5β-androstane; 3α-hydroxy-3β- (4'-methoxyphenyl) ethynyl-17β-methoxy-5β-androstane; 3β- (4'-trifluoro-
methylphenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-chlorophenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-cyanophenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4 '(R / S) -hydroxipentinyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3α-hydroxy-3β-phenyl-17β-methoxy-5β-androstane; 3α-hydroxy-3β-benzyl-17β-methoxy-5β-androstane; 3α-hydroxy-3β- (2'-phenylethyl) -17β-methoxy-5β-androstane; 3α-hydroxy-3β- [2- (3 ', 4'-dimethoxyphenyl) ethyl] -17β-methoxy-5β-androstane; 3α-hydroxy-3β- [6'-oxo-1'-heptinyl] -17β-methoxy-5β-androstane; 3α-hydroxy-3β- (7'-oxo-1'-octinyl) -
17β-methoxy-5β-androstane; 3α-hydroxy-3β- (4'-oxo-1'-pentinyl) -17β-methoxy-5β-androstane; 3β- [5 '- (R / S) -hydroxyhexinyl] -3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-hydroxybutynyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-hydroxybutynyl) -3α-hydroxy-17β-methoxy-5α-androstane; 3β- (4'-acetoxyphenylenyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-acetylphenylethynyl) -3α-hydroxy-19-nor-17β-methoxy-5β-androstane; 3β- (4'-carboxyphenylenyl) -3α-hydroxy-19-nor-17β-methoxy-5β-androstane ethyl ester; 3β- (4'-carboxyphenylethynyl) -3α-hydroxy-17β-methoxy-5α-androstane ethyl ester; 3β- [4 '- (N, N-diethylcarboxamido) phenyl] ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3α-hydroxy-3β- [5-oxo-1-hexinyl] -17β-methoxy-5β-androstane; 3'-hydroxy-3β- [5'-oxo-1'-hexinyl] -17β-methoxy-5β-androstane cyclic 5'- (1,2-ethanediylacetal); 3β- (5-cyano-1-pentinyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3α-hydroxy-3β- (2-pyridyl) ethynyl-17β-
methoxy-5β-androstane; 3β- (6-hydroxy-1-hexinyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3'- (6'-hydroxy-1'-hexinyl) -3α-hydroxy-17β-methoxy-5β-androstane 6'-hemisuccinate sodium salt; 3β- (5'-hydroxy-1'-pentinyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3'- (5'-hydroxy-1'-pentinyl) -3α-hydroxy-17β-methoxy-5β-androstane 5'-hemisuccinate sodium salt; sodium salt of β'- (4'-hydroxy-1'-butynyl) -3α-hydroxy-17β-methoxy-5β-androstane 4'-hemisuccinate; 3β- (4'-cyano-1'-butynyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3β- (5'-acetoxy-1'-pentinyl) -3α-hydroxy-17β-methoxy-5β-an-
drostane; 3β- (4'-acetoxy-1'-butynyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-acetoxy-1'-butynyl) -3α-hydroxy-
17β-methoxy-5α-androstane; 3β- (6'-acetoxy-1'-hexinyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3α-hydroxy-3β- [3- (2'-propynyloxy) -1-propynyl] -17β-methoxy-5β-androstane; 3α-hydroxy-3β- (3-methoxy-1-propynyl) -17β-methoxy-5β-androstane; 3α-hydroxy-3β- (3-methoxy-1-propynyl) -17β-methoxy-5α-androstane; 3α-hydroxy-3β- [3- (4'-pyridinyloxy) -1-propynyl] -17β-methoxy-5β-androstane; 3α-hydroxy-3β- [3- (1'H-1,2,3-triazol-1'-yl) -1-propynyl] -17β-methoxy-5β-androstane; 3α-hydroxy-3β- [3- (2'H-1,2,3-triazol-2'-yl) -1-propynyl] -17β-methoxy-5β-androstane; 3α-hydroxy-3β- (2'-thienyl) ethynyl-17β-methoxy-5β-androstane; 3α-hydroxy-3β- (3'-phenyl-1'-propynyl) -17β-methoxy-5β-androstane; 3α-hydroxy-3β- (3'-phenylpropyl) -17β-methoxy-5β-androstane; 3α-hydroxy-3β- [3- (1'H-pyrazol-1'-yl) -1-propynyl] -17β-methoxy-5β-androstane; 3β- (3'-acetylphenylethynyl) -3α-hydroxy-17β-methoxy-5β-androstane and 3β- (3'-acetoxy-3'-propynyl) -3α-hydroxy -17? -Methoxy-5? -Androstane.
Los esteroides neuroactivos más preferidos de
acuerdo con este aspecto de la presente invención incluyen
3\beta-(4'-acetilfenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano;
éster etílico de
3\beta-(4'-carboxilfenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano;
3\beta-(4'-acetilfenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
éster etílico de
3\beta-(4'-carboxilfenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\beta-(4'-acetilfenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-19-
norandrostano;
éster etílico de
3\beta-(4'-carboxilfenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-19-norandrostano;
3\beta-(4'-dimetilaminofenil)etinil-17\beta-metoxi-5\beta-androstano;
3\beta-(4'-bifenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\alpha-hidroxi-3\beta-(4'-metoxifenil)etinil-17\beta-metoxi-5\beta-androstano;
3\beta-(4'-trifluorometilfenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-
androstano;
3\beta-(4'-clorofenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\beta-[4'(R/S)-hidroxipentinil]-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\beta-(4'-hidroxibutinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano;
3\beta-(4'-hidroxibutinil)-3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano
y
3\alpha-hidroxi-3\beta-[3-(2'H-1,2,3-triazol-2'-il)-1-propinil]-17\beta-metoxi-5\beta-androstano.The most preferred neuroactive steroids in accordance with this aspect of the present invention include 3β- (4'-acetylphenyl) ethynyl-3α-hydroxy-17β-methoxy-5α-androstane; 3β- (4'-carboxyphenyl) ethynyl-3α-hydroxy-17β-methoxy-5α-androstane ethyl ester; 3β- (4'-acetylphenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-carboxyphenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane ethyl ester; 3β- (4'-acetylphenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-19-
norandrostane; 3β- (4'-carboxyphenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-19-norandrostane ethyl ester; 3β- (4'-dimethylaminophenyl) ethynyl-17β-methoxy-5β-androstane; 3β- (4'-biphenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3α-hydroxy-3β- (4'-methoxyphenyl) ethynyl-17β-methoxy-5β-androstane; 3β- (4'-trifluoromethylphenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-
androstane; 3β- (4'-chlorophenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β- [4 '(R / S) -hydroxipentinyl] -3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-hydroxybutynyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-hydroxybutynyl) -3α-hydroxy-17β-methoxy-5α-androstane and 3α-hydroxy-3β- [3- (2'H-1,2 , 3-triazol-2'-yl) -1-propynyl] -17β-methoxy-5β-androstane.
Los esteroides neuroactivos especialmente preferidos de acuerdo con este aspecto de la presente invención incluyen 3\beta-(4'-acetilfenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano; 3\beta-(4'-acetilfenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano; éster etílico de 3\beta-(4'-carboxilfenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano; éster etílico de 3\beta-(4'-carboxifenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano; 3\beta-(4'-dimetilaminofenil)etinil-17\beta-metoxi-5\beta-androstano; 3\beta-(4'-bifenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano; 3\beta-(4'-hidroxibutinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano; 3\beta-(4'-hidroxibutinil)-3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano; 3\alpha-hidroxi-3\beta-[3-(2'H-1,2,3-triazol-2'-il)-1-propinil]-17\beta-metoxi-5\beta-androstano; 3\beta-(4'-acetilfenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-19-norandrostano y 3\beta-[4'(R/S)-hidroxipentinil]-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano.Neuroactive Steroids Especially preferred according to this aspect of the present invention include 3β- (4'-acetylphenyl) ethynyl-3α-hydroxy-17β-methoxy-5α-androstane; 3β- (4'-acetylphenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; ethyl ester of 3β- (4'-carboxyphenyl) ethynyl-3α-hydroxy-17β-methoxy-5α-androstane; ethyl ester of 3β- (4'-carboxyphenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-dimethylaminophenyl) ethynyl-17β-methoxy-5β-androstane; 3β- (4'-biphenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-hydroxybutynyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-hydroxybutynyl) -3α-hydroxy-17β-methoxy-5α-androstane; 3α-hydroxy-3β- [3- (2'H-1,2,3-triazol-2'-yl) -1-propynyl] -17β-methoxy-5β-androstane; 3β- (4'-acetylphenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-19-norandrostane Y 3β- [4 '(R / S) -hydroxipentinyl] -3α-hydroxy-17β-methoxy-5β-androstane.
Los compuestos de acuerdo con la invención pueden prepararse mediante cualquier método conveniente, por ejemplo usando técnicas convencionales tales como las que se describen en Djerassi, Steroid Reactions, Holden-Day, Inc., San Francisco (1963) o Fried y Edwards, Organic Reactions in Steroid Chemistry, Van Nostrand-Reinhold Co., Nueva York (1972).The compounds according to the invention can be prepared by any convenient method, for example using conventional techniques such as those described in Djerassi, Steroid Reactions , Holden-Day, Inc., San Francisco (1963) or Fried and Edwards, Organic Reactions in Steroid Chemistry , Van Nostrand-Reinhold Co., New York (1972).
Los éteres en el carbono 17 de la presente invención se preparan a partir de compuestos hidroxilados en 17\beta mediante métodos bien conocidos por los expertos en la especialidad para preparar éteres a partir de los alcoholes correspondientes. La mayoría de estos métodos se describen en Larock, Comprehensive Organic Transformations VCH Publishers, Nueva York (1989).The ethers in carbon 17 of the present invention are prepared from hydroxylated compounds in 17 [beta] by methods well known to those skilled in the art for preparing ethers from the corresponding alcohols. Most of these methods are described in Larock, Comprehensive Organic Transformations VCH Publishers, New York (1989).
Los materiales de partida hidroxilados en 17\beta son bien conocidos para los expertos en la especialidad. Es aconsejable proteger el grupo ceto en 3 mediante la formación previa de un cetal. El cetal puede hacerse reaccionar a continuación mediante métodos conocidos para formar el éter en el carbono 17 y el cetal hidrolizarse para obtener los compuestos de 3-ceto-17-éter. Diversos nucleófilos pueden añadirse a la 3-ona de estos compuestos para obtener los derivados substituidos en 3\beta-3\alpha-hidroxi-C17-éter.The hydroxylated starting materials in 17β are well known to those skilled in the art. It is advisable to protect the keto group in 3 by forming previous of a ketal. The ketal can be reacted to then by known methods to form the ether in the carbon 17 and the ketal hydrolyze to obtain the compounds of 3-keto-17-ether. Miscellaneous nucleophiles can be added to the 3-one of these compounds to obtain the substituted derivatives in 3β-3α-hydroxy-C17-ether.
Otro método para obtener los éteres en el carbono 17 es mediante la reacción de cetales en el carbono 17, obtenidos a partir de las correspondientes C17-onas, con hidróxido de litio y aluminio y AlCl_{3} según se describe por Cross y otros, Steroids 5:557 (1965).Another method of obtaining the ethers in carbon 17 is by reacting ketals in carbon 17, obtained from the corresponding C17-ones, with lithium aluminum hydroxide and AlCl 3 as described by Cross et al. Steroids 5 : 557 (1965).
Los substituyentes feniletinilo pueden prepararse mediante el acoplamiento catalizado con paladio (Pd) de los derivados etinílicos correspondientes con yoduros de fenilo o bromuros de fenilo en presencia de una amina.Phenylethylyl substituents can be prepared by palladium catalyzed coupling (Pd) of the corresponding ethinyl derivatives with phenyl iodides or phenyl bromides in the presence of an amine.
Los compuestos de y usados en la invención, que son las formas de acción directa y de "profármaco", naturales y sintéticas, farmacéuticamente aceptables, atóxicas, de derivados esteroideos, tienen hasta ahora una actividad desconocida en el cerebro en el complejo receptor de GABA_{A}. La presente invención se beneficia del descubrimiento de este mecanismo y esta actividad previamente desconocidos.The compounds of and used in the invention, which are the forms of direct and "prodrug" action, natural and synthetic, pharmaceutically acceptable, non-toxic, derivatives Steroids, so far have an unknown activity in the brain in the GABA A receptor complex. The present invention benefits from the discovery of this mechanism and this activity previously unknown.
Las composiciones farmacéuticas de esta invención se preparan en formas unitarias de dosificación convencionales incorporando un compuesto activo de la invención o una mezcla de tales compuestos con un portador farmacéutico atóxico de acuerdo con procedimientos aceptados en una cantidad atóxica suficiente para producir la actividad farmacodinámica deseada en un sujeto, animal o humano. Preferiblemente, la composición contiene el ingrediente activo en una cantidad activa pero atóxica seleccionada de aproximadamente 1 mg a aproximadamente 500 mg de ingrediente activo por unidad de dosificación. Esta cantidad depende de la actividad biológica específica deseada y la condición del paciente.The pharmaceutical compositions of this invention they are prepared in conventional unit dosage forms incorporating an active compound of the invention or a mixture of such compounds with a non-toxic pharmaceutical carrier according with procedures accepted in a non-toxic amount sufficient to produce the desired pharmacodynamic activity in a subject, animal or human Preferably, the composition contains the ingredient. active in an active but non-toxic amount selected from about 1 mg to about 500 mg of active ingredient per dosage unit. This amount depends on the activity. specific biological desired and the patient's condition.
El portador farmacéutico empleado puede ser, por ejemplo, un sólido, un líquido o una liberación temporal (véase, por ejemplo, Remington's Pharmaceutical Sciences, 14ª edición (1970)). Portadores sólidos representativos son lactosa, alabastro, sacarosa, talco, gelatina, agar, pectina, goma arábiga, estearato magnésico, ácido esteárico, celulosa microcristalina, hidrogeles polímeros y similares. Portadores líquidos típicos son propilenglicol, glicofurol, soluciones acuosas de ciclodextrinas, jarabe, aceite de cacahuete y aceite de oliva y emulsiones similares. De forma similar, el portador o diluyente puede incluir cualquier material de retardo temporal bien conocido en la especialidad, tal como monoestearato de glicerol o diestearato de glicerol solo o con cera, microcápsulas, microesferas, liposomas y/o hidrogeles.The pharmaceutical carrier employed can be, for example, a solid, a liquid or a temporary release (see, for example, Remington's Pharmaceutical Sciences , 14th edition (1970)). Representative solid carriers are lactose, alabaster, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid, microcrystalline cellulose, polymer hydrogels and the like. Typical liquid carriers are propylene glycol, glycolurol, aqueous solutions of cyclodextrins, syrup, peanut oil and olive oil and similar emulsions. Similarly, the carrier or diluent may include any time delay material well known in the art, such as glycerol monostearate or glycerol distearate alone or with wax, microcapsules, microspheres, liposomes and / or hydrogels.
Puede emplearse una amplia variedad de formas farmacéuticas. Así, cuando se usa un portador sólido, la preparación puede molerse en molino ordinario, micronizarse, en aceite, formarse como tabletas, ponerse en una cápsulas de gelatina dura o revestida entéricamente en forma de polvos micronizados o nódulos, o en la forma de una pastilla o gragea. La composición de la presente invención también puede administrarse en forma de supositorios para la administración rectal. Los compuestos pueden mezclarse en un material tal como mantequilla de cacao y polietilenglicoles u otro material no irritante adecuado que sea sólido a temperatura ambiente pero líquido a la temperatura rectal. Cuando se usa un portador líquido, la preparación puede estar en la forma de un líquido, tal como una ampolla, o como una suspensión líquida acuosa o no acuosa. Las formas de dosificación líquidas también necesitan conservantes farmacéuticamente aceptables. Además, debido a las bajas dosis requeridas, basándose en los datos descritos aquí, la administración parenteral, la pulverización nasal, la administración sublingual y bucal y los parches cutáneos de liberación temporizada también son formas farmacéuticas adecuadas para la administración tópica.A wide variety of ways can be used Pharmaceuticals Thus, when a solid carrier is used, the Preparation can be milled in ordinary mill, micronized, in oil, form as tablets, put in a gelatin capsules hard or enteric coated in the form of micronized powders or nodules, or in the form of a pill or dragee. The composition of The present invention can also be administered in the form of suppositories for rectal administration. The compounds can mix in a material such as cocoa butter and polyethylene glycols or other suitable non-irritating material that is solid at room temperature but liquid at rectal temperature. When a liquid carrier is used, the preparation may be in the form of a liquid, such as a blister, or as a suspension aqueous or non-aqueous liquid. Liquid dosage forms They also need pharmaceutically acceptable preservatives. In addition, due to the low doses required, based on data described here, parenteral administration, spraying nasal, sublingual and oral administration and skin patches Timed release are also suitable pharmaceutical forms for topical administration.
El método para producir actividad ansiolítica, anticonvulsiva, alteradora del estado de ánimo (tal como antidepresiva) o hipnótica, de acuerdo con esta invención, comprende administrar a un sujeto que necesite tal actividad un compuesto de la invención, habitualmente preparado en una composición como la descrita previamente con un portador farmacéutico, en una cantidad atóxica suficiente para producir dicha actividad.The method to produce anxiolytic activity, anticonvulsant, mood disorder (such as antidepressant) or hypnotic, according to this invention, comprises administering to a subject that needs such activity a compound of the invention, usually prepared in a composition as previously described with a carrier pharmacist, in a non-toxic quantity sufficient to produce such activity
Durante la menstruación, los niveles de metabolitos de progesterona excretados varían aproximadamente cuatro veces (Rosciszewska y otros, J. Neurol. Neurosurg. Psych. 49:47-51 (1986)). Por lo tanto, la terapia para controlar los síntomas implica mantener a la paciente a un nivel superior de metabolitos de progesterona que el normal en el estado premenstrual de pacientes con PMS. Los niveles en plasma de metabolitos activos y principales se controlan durante la premenstruación y la postmenstruación de la paciente. La cantidad de los compuestos de la invención administrados, solos o como mezclas de los mismos, se calcula así para alcanzar un nivel que ejercerá una actividad receptora de GABA_{A} igual o superior que el nivel de metabolitos de progesterona en el sujeto normal durante el estado premenstrual.During menstruation, the levels of excreted progesterone metabolites vary approximately four times (Rosciszewska et al., J. Neurol. Neurosurg. Psych. 49 : 47-51 (1986)). Therefore, therapy to control symptoms involves keeping the patient at a higher level of progesterone metabolites than normal in the premenstrual state of patients with PMS. Plasma levels of active and main metabolites are controlled during the premenstruation and postmenstruation of the patient. The amount of the compounds of the invention administered, alone or as mixtures thereof, is thus calculated to reach a level that will exert a GABA A receptor activity equal to or greater than the level of progesterone metabolites in the normal subject during the premenstrual state.
El método para inducir el sueño y mantener substancialmente el nivel de sueño REM que se encuentra en el sueño normal, en donde no se induce un insomnio de rebote substancial, de acuerdo con la presente invención, comprende administrar a un sujeto que necesite tal actividad una cantidad eficaz de un derivado esteroideo descrito aquí. Los compuestos de la invención son capaces de incrementar el sueño NREM y el período de sueño total, sin afectar substancialmente a la cantidad de sueño REM. El insomnio de rebote se define como la reducción del sueño NREM después de que la acción hipnótica del tratamiento haya vuelto hasta niveles de control. Métodos para evaluar los efectos de los compuestos de la invención sobre el sueño REM y NREM se describen en WO94/27608, publicada el 8 de Diciembre de 1994, cuyo contenido se incorpora totalmente mediante referencia aquí.The method to induce sleep and maintain substantially the level of REM sleep found in sleep normal, where substantial rebound insomnia is not induced, of according to the present invention, comprises administering to a subject needing such activity an effective amount of a derivative Steroid described here. The compounds of the invention are capable of increasing NREM sleep and total sleep period, without substantially affecting the amount of REM sleep. He Bounce insomnia is defined as NREM sleep reduction after the hypnotic treatment action has returned Up to control levels. Methods to assess the effects of compounds of the invention on REM and NREM sleep are described in WO94 / 27608, published on December 8, 1994, whose content It is fully incorporated by reference here.
La ruta de administración puede ser cualquier ruta que transporte eficazmente el compuesto activo a los receptores de GABA_{A} que han de estimularse. La administración puede llevarse a cabo parenterlamente, enteralmente, rectalmente, intravaginalmente, intradérmicamente, intramuscularmente, sublingualmente o nasalmente; se prefieren las rutas oral, intramuscular y dérmica. Por ejemplo, una dosis en un parche cutáneo puede suministrar el ingrediente activo al paciente durante un período de hasta una semana. Sin embargo, la ruta parenteral se prefiere para estados epilépticos.The administration route can be any route that effectively transports the active compound to GABA receptors to be stimulated. The administration it can be carried out parenterally, enterally, rectally, intravaginally, intradermally, intramuscularly, sublingually or nasally; oral routes are preferred, intramuscular and dermal. For example, a dose in a patch The skin can supply the active ingredient to the patient during A period of up to a week. However, the parenteral route is Prefer for epileptic states.
Los siguientes ejemplos son ilustrativos, pero no
limitativos, del método y las composiciones de la presente
invención. Otras modificaciones y adaptaciones adecuadas de la
variedad de condiciones y parámetros encontrados normalmente y
obvias para los expertos en la especialidad están dentro del
espíritu y el alcance de la inven-
ción.The following examples are illustrative, but not limiting, of the method and compositions of the present invention. Other modifications and appropriate adaptations of the variety of conditions and parameters normally found and obvious to those skilled in the art are within the spirit and scope of the invention.
tion.
Una solución de 2-metil-1-buten-3-ino (150 mg, 0,21 ml, 2,25 milimoles) en THF seco (20 ml) se trató con n-BuLi (2,5 M en THF, 2,25 milimoles, 0,9 ml) a -70ºC. Después de agitar la mezcla a -75ºC durante 0,5 horas, se añadió una solución de 17\beta-metoxi-5\beta-androstan-3-ona (228 mg, 0,75 milimoles) en THF (20 ml) y la mezcla se agitó a -78ºC durante 30 minutos. El baño de enfriamiento se retiró y la mezcla se extinguió con solución de NH_{4}Cl (2 ml). Los disolventes se retiraron y el residuo se extrajo con EtOAc. La capa orgánica se lavó con agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el producto en bruto. Este producto en bruto se disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de sílice. La elución con una mezcla de hexano:acetona (9:1) daba 3\alpha-Hidroxi-17\beta-metoxi-3\beta-(3'-metilbut-3'-en-1'-inil)-5\beta-androstano (133 mg) como un sólido incoloro; pf 145-147ºC; TLC R_{f} (hexano:acetona 85:15) = 0,21.A solution of 2-methyl-1-buten-3-ino (150 mg, 0.21 ml, 2.25 mmol) in dry THF (20 ml) was treated with n-BuLi (2.5 M in THF, 2.25 mmol, 0.9 ml) a -70 ° C. After stirring the mixture at -75 ° C for 0.5 hours, it is added a solution of 17β-methoxy-5β-androstan-3-one (228 mg, 0.75 mmol) in THF (20 ml) and the mixture was stirred at -78 ° C for 30 minutes. The cooling bath was removed and the mixture was quenched with NH 4 Cl solution (2 ml). The Solvents were removed and the residue was extracted with EtOAc. The layer Organic washed with water and brine. After drying over MgSO4 anhydrous, the solution was filtered and evaporated to give the raw product. This crude product was dissolved at then in a small amount of CH2Cl2 and it was poured on a column of silica gel. Elution with a mixture of hexane: acetone (9: 1) gave 3α-Hydroxy-17β-methoxy-3β- (3'-methylbut-3'-en-1'-inyl) -5β-androstane (133 mg) as a colorless solid; mp 145-147 ° C; FTA R f (hexane: acetone 85:15) = 0.21.
Una solución de 3-butin-1-ol (0,114 ml, 1,5 milimoles) en THF seco (15 ml) se trató con n-BuLi (1,2 ml, 2,5M en THF, 3 milimoles) a -75ºC. Después de agitar la mezcla a 78ºC durante 0,5 horas, se añadió una solución de 17\beta-metoxi-5\beta-androstan-3-ona (152 mg, 0,5 milimoles) en THF (20 ml) y la mezcla se agitó a -78ºC durante 5 minutos. El baño de enfriamiento se retiró a continuación y la agitación se continuó a temperatura ambiente durante 45 minutos. La mezcla se extinguió a continuación con solución de NH_{4}Cl (5 ml). Los disolventes se retiraron y el residuo se extrajo con EtOAc. La capa orgánica se lavó con agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el producto en bruto. Este producto en bruto se disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de sílice. La elución con mezcla de tolueno:acetona (4:1) daba 3\alpha-(4'-hidroxi-1'-butinil)-3\beta-hidroxi-17\beta-metoxi-5\beta-androstano (20 mg), y a continuación 3\beta-(4'-hidroxi-1'-butinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano (70 mg) como un sólido incoloro; pf 132-134ºC; TLC R_{f} (tolueno:acetona 4:1) = 0,19.A solution of 3-butin-1-ol (0.114 ml, 1.5 millimoles) in dry THF (15 ml) was treated with n-BuLi (1.2 ml, 2.5M in THF, 3 mmol) at -75 ° C. After stirring the mixture at 78 ° C for 0.5 hours, a solution of 17β-methoxy-5β-androstan-3-one (152 mg, 0.5 mmol) in THF (20 ml) and the mixture was stirred at -78 ° C for 5 minutes. The cooling bath was then removed. and stirring was continued at room temperature for 45 minutes The mixture was then quenched with solution of NH 4 Cl (5 ml). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water and brine. After drying over anhydrous MgSO4, the solution was filtered and It was evaporated to give the crude product. This raw product is then dissolved in a small amount of CH2Cl2 and poured into a column of silica gel. Elution with mixing of toluene: acetone (4: 1) gave 3α- (4'-hydroxy-1'-butynyl) -3β-hydroxy-17β-methoxy-5β-androstane (20 mg), and then 3β- (4'-hydroxy-1'-butynyl) -3α-hydroxy-17β-methoxy-5β-androstane (70 mg) as a colorless solid; mp 132-134 ° C; FTA R f (toluene: acetone 4: 1) = 0.19.
Una solución de 3\beta-(4'-hidroxi-1'-butinil)-3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano (350 mg, 0,93 milimoles) en piridina (6 ml) se trató con anhídrido succínico (372 mg, 3,7 milimoles) y 4-(N,N-dimetil)aminopiridina (20 mg). La mezcla se calentó hasta 70-75ºC durante 3 horas. La TLC mostraba 100% de conversión. Se enfrió hasta temperatura ambiente y se vertió en hielo-HCl 2N. Los materiales orgánicos se extrajeron con EtOAc. La capa orgánica se lavó con HCl 0,2N, agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el producto en bruto. Este producto en bruto se disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de sílice. La elución con mezcla de hexano:acetona (7:3) daba 4'-hemisuccinato de 3\beta-(4'-hidroxi-1'-butinil)-3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano (360 mg).A solution of 3β- (4'-hydroxy-1'-butynyl) -3α-hydroxy-17β-methoxy-5α-androstane (350 mg, 0.93 mmol) in pyridine (6 ml) was treated with anhydride succinic (372 mg, 3.7 mmol) and 4- (N, N-dimethyl) aminopyridine (20 mg). The mixture was heated to 70-75 ° C for 3 hours. The TLC showed 100% conversion. Cooled to temperature ambient and poured into ice-2N HCl. The Organic materials were extracted with EtOAc. The organic layer is washed with 0.2N HCl, water and brine. After drying over MgSO4 anhydrous, the solution was filtered and evaporated to give the raw product. This crude product was dissolved at then in a small amount of CH2Cl2 and it poured into a column of silica gel. Elution with mixture of hexane: acetone (7: 3) gave 4'-hemisuccinate of 3β- (4'-hydroxy-1'-butynyl) -3α-hydroxy-17β-methoxy-5α-androstane (360 mg)
Una mezcla del hemisuccinato previo (360 mg, 0,76 milimoles), NaHCO_{3} (64 mg, 0,76 milimoles), agua (3 ml) y CH_{2}Cl_{2} (5 ml) se agitó a temperatura ambiente durante 1 hora. El disolvente se retiró y el residuo se suspendió en acetona (5 ml). El sólido blanco se recogió a continuación mediante filtración y se secó para dar la sal sódica como un sólido incoloro (210 mg).A mixture of the previous hemisuccinate (360 mg, 0.76 millimoles), NaHCO3 (64 mg, 0.76 mmol), water (3 ml) and CH 2 Cl 2 (5 ml) was stirred at room temperature for 1 hour. The solvent was removed and the residue was suspended in acetone (5 ml). The white solid was then collected by filtration and dried to give the sodium salt as a colorless solid (210 mg).
Una solución de 3-butin-1-ol (0,15 ml, 2 milimoles) en THF seco (15 ml) se trató con n-BuLi (1,6 ml, 2,5M en THF, 4 milimoles) a -75ºC. Después de agitar la mezcla a -78ºC durante 0,5 horas, se añadió una solución de 17\beta-metoxi-5\alpha-androstan-3-ona (304 mg, 1 milimol) en THF (20 ml) y la mezcla se agitó a -78ºC durante 5 minutos. El baño de enfriamiento se retiró a continuación y la agitación se continuó a temperatura ambiente durante 45 minutos. La mezcla se extinguió a continuación con solución de NH_{4}Cl (5 ml). Los disolventes se retiraron y el residuo se extrajo con EtOAc. La capa orgánica se lavó con agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el producto en bruto. Este producto en bruto se disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de sílice. La elución con mezcla de tolueno:acetona (4:1) daba 3\beta-(4'-hidroxi-1'-butinil)-3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano (50 mg); pf 184-186ºC; TLC R_{f} (tolueno:acetona 4:1) = 0,35; y a continuación 3\alpha-(4'-hidroxi-1'-butinil)-3\beta-hidroxi-17\beta-metoxi-5\alpha-androstano (225 mg) como un sólido incoloro; pf 185-187ºC; TLC R_{f} (tolueno:acetona 4:1) = 0,24.A solution of 3-butin-1-ol (0.15 ml, 2 millimoles) in dry THF (15 ml) was treated with n-BuLi (1.6 ml, 2.5M in THF, 4 millimoles) at -75 ° C. After stirring the mixture at -78 ° C for 0.5 hour, a solution of 17β-methoxy-5α-androstan-3-one (304 mg, 1 mmol) in THF (20 ml) and the mixture was stirred at -78 ° C for 5 minutes. The cooling bath was then removed. and stirring was continued at room temperature for 45 minutes The mixture was then quenched with solution of NH 4 Cl (5 ml). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water and brine. After drying over anhydrous MgSO4, the solution was filtered and It was evaporated to give the crude product. This raw product is then dissolved in a small amount of CH2Cl2 and poured into a column of silica gel. Elution with mixing of toluene: acetone (4: 1) gave 3β- (4'-hydroxy-1'-butynyl) -3α-hydroxy-17β-methoxy-5α-androstane (50 mg); mp 184-186 ° C; TLC R f (toluene: acetone 4: 1) = 0.35; and then 3α- (4'-hydroxy-1'-butynyl) -3β-hydroxy-17β-methoxy-5α-androstane (225 mg) as a colorless solid; mp 185-187 ° C; FTA R f (toluene: acetone 4: 1) = 0.24.
Una solución de
17\beta-metoxi-5\alpha-androstan-3-ona
(101 mg, 0,33 milimoles) en THF seco (20 ml) se trató con MeLi (1
ml, 1,5M en THF, 1,5 milimoles) a -75ºC. Después de agitar la mezcla
a -78ºC durante 0,5 horas, la mezcla se extinguió con solución de
NH_{4}Cl (5 ml). Los disolventes se retiraron y el residuo se
extrajo con EtOAc. La capa orgánica se lavó con agua y salmuera.
Después de secar sobre MgSO_{4} anhidro, la solución se filtró y
se evaporó para dar el producto en bruto. Este producto en bruto se
disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2}
y se vertió en una columna de gel de sílice. La elución con mezcla
de tolueno:acetona (95:5) daba
3\beta-metil-3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano
(35 mg); pf 151-154ºC; TLC R_{f} (hexano:acetona
7:3) = 0,43; y a continuación
3\alpha-metil-3\beta-hidroxi-17\beta-metoxi-5\alpha-androstano
(30 mg) como un sólido incoloro; TLC R_{f} (hexano:acetona 7:3)
=
0,27.A solution of 17β-methoxy-5α-androstan-3-one (101 mg, 0.33 mmol) in dry THF (20 ml) was treated with MeLi (1 ml, 1.5M in THF, 1, 5 millimoles) at -75 ° C. After stirring the mixture at -78 ° C for 0.5 hours, the mixture was quenched with NH 4 Cl solution (5 ml). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water and brine. After drying over anhydrous MgSO4, the solution was filtered and evaporated to give the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured onto a silica gel column. Elution with toluene: acetone mixture (95: 5) gave 3β-methyl-3α-hydroxy-17β-methoxy-5α-androstane (35 mg); mp 151-154 ° C; TLC R f (hexane: acetone 7: 3) = 0.43; and then 3α-methyl-3β-hydroxy-17β-methoxy-5α-androstane (30 mg) as a colorless solid; TLC R f (hexane: acetone 7: 3) =
0.27.
Una solución de 17\beta-metoxi-5\alpha-androstan-3-ona (220 mg, 0,75 milimoles) en THF seco (20 ml) se trató con trifluorometiltrimetilsilano (3 ml, 0,5M en THF, 1,5 milimoles) y fluoruro de tetrabutilamonio (TBAF) (10 mg) a 0ºC. Después de agitar la mezcla a 23ºC durante 2 horas, la mezcla volvió a enfriarse hasta 0ºC. Se añadió una solución de TBAF (1M en THF, 2 ml, 2 milimoles). La mezcla se agitó a temperatura ambiente durante 10 minutos, se extinguió con solución de NH_{4}Cl (5 ml). Los disolventes se retiraron y el residuo se extrajo con EtOAc. La capa orgánica se lavó con agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el producto en bruto. Este producto en bruto se disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de sílice. La elución con mezcla de hexano:acetato de etilo (9:1) daba 3\beta-trifluorometil-3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano (9 mg); TLC R_{f} (hexano:EtOAc 8:2) = 0,51; y a continuación 3\alpha-trifluorometil-3\beta-hidroxi-17\beta-metoxi-5\alpha-androstano (170 mg) como un sólido incoloro; TLC R_{f} (hexano:EtOAc 8:2) = 0,45.A solution of 17β-methoxy-5α-androstan-3-one (220 mg, 0.75 mmol) in dry THF (20 ml) was treated with trifluoromethyltrimethylsilane (3 ml, 0.5M in THF, 1.5 mmol) and tetrabutylammonium fluoride (TBAF) (10 mg) at 0 ° C. After stirring the mixture at 23 ° C for 2 hours, the mixture was cooled again until 0 ° C A solution of TBAF (1M in THF, 2 ml, 2 mmol) was added. The mixture was stirred at room temperature for 10 minutes, it was quenched with NH4Cl solution (5 ml). The solvents are removed and the residue was extracted with EtOAc. The organic layer is washed with water and brine. After drying over anhydrous MgSO4, The solution was filtered and evaporated to give the crude product. This crude product was then dissolved in a small amount of CH 2 Cl 2 and was poured into a gel column of silica. Elution with hexane mixture: ethyl acetate (9: 1) gave 3β-trifluoromethyl-3α-hydroxy-17β-methoxy-5α-androstane (9 mg); TLC R f (hexane: EtOAc 8: 2) = 0.51; and then 3α-trifluoromethyl-3β-hydroxy-17β-methoxy-5α-androstane (170 mg) as a colorless solid; TLC R f (hexane: EtOAc 8: 2) = 0.45.
Una solución de 17\beta-metoxi-5\beta-androstan-3-ona (304 mg, 1 milimol) en THF seco (20 ml) se trató con trifluorometiltrimetilsilano (7 ml, 0,5M en THF, 3,5 milimoles) y TBAF (10 mg) a 0ºC. Después de agitar la mezcla a 23ºC durante 2 horas, la mezcla volvió a enfriarse hasta 0ºC. Se añadió una solución de TBAF (1M en THF, 3,5 ml, 3,5 milimoles). La mezcla se agitó a temperatura ambiente durante 10 minutos y a continuación se extinguió con solución de NH_{4}Cl (5 ml). Los disolventes se retiraron y el residuo se extrajo con EtOAc. La capa orgánica se lavó con agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el producto en bruto. Este producto en bruto se disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de sílice. La elución con mezcla de hexano:acetato de etilo (9:1) daba 3\beta-trifluorometil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano (220 mg); pf 122-127ºC; TLC R_{f} (hexano:EtOAc 8:2) = 0,38.A solution of 17β-methoxy-5β-androstan-3-one (304 mg, 1 mmol) in dry THF (20 ml) was treated with trifluoromethyltrimethylsilane (7 ml, 0.5M in THF, 3.5 mmol) and TBAF (10 mg) at 0 ° C. After stirring the mixture at 23 ° C for 2 hours, the mixture was cooled again to 0 ° C. Added one TBAF solution (1M in THF, 3.5 ml, 3.5 mmol). The mixture is stirred at room temperature for 10 minutes and then quenched with NH4Cl solution (5 ml). The solvents are removed and the residue was extracted with EtOAc. The organic layer is washed with water and brine. After drying over anhydrous MgSO4, The solution was filtered and evaporated to give the crude product. This crude product was then dissolved in a small amount of CH 2 Cl 2 and was poured into a gel column of silica. Elution with hexane mixture: ethyl acetate (9: 1) gave 3β-trifluoromethyl-3α-hydroxy-17β-methoxy-5β-androstane (220 mg); mp 122-127 ° C; TLC R f (hexane: EtOAc 8: 2) = 0.38.
Ejemplo de Referencia 8Reference Example 8
Una solución de 17\beta-metoxi-5\beta-androstan-3-ona (130 mg, 0,42 milimoles) en THF seco (15 ml) se trató con hidruro de litio y tri(terc-butoxi)aluminio (1 ml, 1M en THF, 1 milimol) a -73ºC. Después de agitar la mezcla a -75ºC durante 3 horas y a continuación a -10ºC durante 1,5 horas, la mezcla se extinguió con solución de NaOH (1N, 2 ml). Los disolventes se retiraron y el residuo se extrajo con EtOAc. La capa orgánica se lavó con agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el producto en bruto. Este producto en bruto se disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de sílice. La elución con mezcla de tolueno:acetona (9:1) daba 3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano (107 mg); pf 151-156ºC; TLC R_{f} (hexano:acetona 7:3) = 0,18.A solution of 17β-methoxy-5β-androstan-3-one (130 mg, 0.42 mmol) in dry THF (15 ml) was treated with hydride lithium and tri (tert-butoxy) aluminum (1 ml, 1M in THF, 1 millimol) at -73 ° C. After stirring the mixture at -75 ° C for 3 hours and then at -10 ° C for 1.5 hours, The mixture was quenched with NaOH solution (1N, 2 ml). The Solvents were removed and the residue was extracted with EtOAc. The layer Organic washed with water and brine. After drying over MgSO4 anhydrous, the solution was filtered and evaporated to give the raw product. This crude product was dissolved at then in a small amount of CH2Cl2 and it was poured on a column of silica gel. Elution with mixture of toluene: acetone (9: 1) gave 3α-hydroxy-17β-methoxy-5β-androstane (107 mg); mp 151-156 ° C; TLC R f (hexane: acetone 7: 3) = 0.18.
Ejemplo de Referencia 9Reference Example 9
Una solución de 3-(1,2-etanodiilacetal) cíclico de 17\beta-hidroxi-5\alpha-androstan-3-ona ( (1,03 g, 3 milimoles) en THF seco (20 ml) se trató con KOt-Bu (12 ml, 1M en THF, 12 milimoles) a 23ºC. Después de agitar la mezcla a 55ºC durante 2,5 horas, se enfrió hasta -50ºC. Se añadió bromuro de propargilo (solución al 80% en tolueno, 1,3 ml, 11 milimoles) y la agitación se continuó a 50-55ºC durante 2,5 horas. Los disolvente se retiraron y el residuo se trató con acetona (25 ml). Después de acidificar la mezcla con HCl 2N, se agitó a temperatura ambiente durante 15 horas. La mezcla se neutralizó con solución de NaOH 2N. Los disolventes se retiraron y el residuo se extrajo con EtOAc. La capa orgánica se lavó con agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el producto en bruto. Este producto en bruto se disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de sílice. La elución con mezcla de hexano:acetona (8:2) daba 17\beta-(2-propiniloxi)-5\alpha-androstan-3-ona (700 mg).A solution of 3- (1,2-1,2-ethanediyl acetal) cyclic of 17β-hydroxy-5α-androstan-3-one ((1.03 g, 3 mmol) in dry THF (20 ml) was treated with KOt-Bu (12 ml, 1M in THF, 12 mmol) at 23 ° C. After stirring the mixture at 55 ° C for 2.5 hours, it was cooled up to -50 ° C. Propargyl bromide (80% solution in toluene, 1.3 ml, 11 mmol) and stirring was continued at 50-55 ° C for 2.5 hours. The solvents are removed and the residue was treated with acetone (25 ml). After acidify the mixture with 2N HCl, stirred at room temperature for 15 hours The mixture was neutralized with 2N NaOH solution. The solvents were removed and the residue was extracted with EtOAc. The Organic layer was washed with water and brine. After drying over MgSO4 anhydrous, the solution was filtered and evaporated to give the raw product. This crude product was dissolved at then in a small amount of CH2Cl2 and it poured into a column of silica gel. Elution with mixture of hexane: acetone (8: 2) gave 17β- (2-propynyloxy) -5α-androstan-3-one (700 mg).
Ejemplo de Referencia 10Reference Example 10
Una solución de 17\beta-(2-propiniloxi)-5\alpha-androstan-3-ona (230 mg, 0,7 milimoles) en THF seco (20 ml) se trató con MeLi (5 ml, 1M en THF, 5 milimoles) a -70ºC. Después de agitar la mezcla a -70ºC durante 0,5 horas, el baño de enfriamiento se retiró y se calentó hasta 10ºC. La mezcla se extinguió a continuación con solución de NH_{4}Cl (5 ml). Los disolventes se retiraron y el residuo se extrajo con EtOAc. La capa orgánica se lavó con agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el producto en bruto. Este producto en bruto se disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de sílice. La elución con mezcla de tolueno:acetona (98:2) daba 3\alpha-hidroxi-3\beta-metil-17\beta-(2-propiniloxi)-5\alpha-androstano (40 mg); TLC R_{f} (tolueno:acetona 95:5) = 0,31; y a continuación 3\beta-hidroxi-3\alpha-metil-17\beta-(2-propiniloxi)-5\alpha-androstano (70 mg) como un sólido incoloro; TLC R_{f} (hexano:acetona 7:3) = 0,27.A solution of 17β- (2-propynyloxy) -5α-androstan-3-one (230 mg, 0.7 mmol) in dry THF (20 ml) was treated with MeLi (5 ml, 1M in THF, 5 millimoles) at -70 ° C. After stirring the mixture to -70 ° C for 0.5 hours, the cooling bath was removed and heated to 10 ° C. The mixture was then extinguished with NH 4 Cl solution (5 ml). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water and brine. After drying over anhydrous MgSO4, the solution is filtered and evaporated to give the crude product. This product in crude was then dissolved in a small amount of CH 2 Cl 2 and was poured onto a silica gel column. The elution with toluene mixture: acetone (98: 2) gave 3α-hydroxy-3β-methyl-17β- (2-propynyloxy) -5α-androstane (40 mg); TLC Rf (toluene: acetone 95: 5) = 0.31; already continuation 3β-hydroxy-3α-methyl-17β- (2-propynyloxy) -5α-androstane (70 mg) as a colorless solid; TLC R f (hexane: acetone 7: 3) = 0.27.
Ejemplo de Referencia 11Reference Example eleven
Una solución de 4-yodoacetofenona (16 mg, 0,06 milimoles) y 3\alpha-hidroxi-3\beta-metil-17\beta-(2-propiniloxi)-5\alpha-androstano (22 mg, 0,06 milimoles) en trietilamina desgasificada seca (1 ml) se agitó bajo argón a 23ºC. Se añadieron cloruro de bis(trifenilfosfina)paladio (2 mg) y CuI (2 mg) y la mezcla se agitó a esta temperatura durante 45 minutos. Se añadió CH_{2}Cl_{2} (4 ml) y la mezcla se agitó a 23ºC durante 1 hora. La TLC mostraba 100% de conversión del material de partida, de ahí que el disolvente se retirara y el residuo se purificara mediante cromatografía sobre gel de sílice. La elución con hexano:acetona (85:15) daba 17\beta-[3-(4-acetilfenil)-2-propiniloxi]-3\alpha-hidroxi-3\beta-metil-5\alpha-androstano (19 mg) como un sólido incoloro; pf 52-55ºC; TLC R_{f} (hexano:acetona 85:15) = 0,15.A solution of 4-iodoacetophenone (16 mg, 0.06 mmol) and 3α-hydroxy-3β-methyl-17β- (2-propynyloxy) -5α-androstane (22 mg, 0.06 mmol) in dry degassed triethylamine (1 ml) stirred under argon at 23 ° C. Chloride was added bis (triphenylphosphine) palladium (2 mg) and CuI (2 mg) and the The mixture was stirred at this temperature for 45 minutes. Was added CH 2 Cl 2 (4 ml) and the mixture was stirred at 23 ° C for 1 hour. The FTA showed 100% conversion of the starting material, hence that the solvent is removed and the residue is purified by silica gel chromatography. Elution with hexane: acetone (85:15) It gave 17β- [3- (4-acetylphenyl) -2-propynyloxy] -3α-hydroxy-3β-methyl-5α-androstane (19 mg) as a colorless solid; mp 52-55 ° C; FTA R f (hexane: acetone 85:15) = 0.15.
Ejemplo de Referencia 12Reference Example 12
Una solución de 17-(1,2-etanodiilacetal) cíclico de 3\alpha-hidroxi-5\alpha-androstan-17-ona (166 mg, 0,5 milimoles) en THF seco (10 ml) se trató con LAH (18 mg, 0,5 milimoles) y AlCl_{3} (266 mg, 2 milimoles) a 23ºC. Después de agitar la mezcla a 45ºC durante 2 horas, se extinguió con solución de NH_{4}Cl (2 ml). Los disolventes se retiraron y el residuo se extrajo con EtOAc. La capa orgánica se lavó con HCl diluido, agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el producto en bruto. Este producto en bruto se disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de sílice. La elución con mezcla de hexano:acetona (8:2) daba 17\beta-(2-hidroxietoxi)-3\alpha-hidroxi-5\alpha-androstano (123 mg); pf 181-183ºC; TLC R_{f} (hexano:acetona 7:3) = 0,31.A solution of Cyclic 17- (1,2-ethanediilacetal) of 3α-hydroxy-5α-androstan-17-one (166 mg, 0.5 mmol) in dry THF (10 ml) was treated with LAH (18 mg, 0.5 mmol) and AlCl 3 (266 mg, 2 mmol) at 23 ° C. After stirring the mixture at 45 ° C for 2 hours, it was quenched with NH 4 Cl solution (2 ml). The solvents were removed and The residue was extracted with EtOAc. The organic layer was washed with HCl diluted, water and brine. After drying over MgSO4 anhydrous, the solution was filtered and evaporated to give the product in stupid. This crude product was then dissolved in a small amount of CH2Cl2 and was poured into a column of Silica gel. Elution with hexane mixture: acetone (8: 2) gave 17β- (2-hydroxyethoxy) -3α-hydroxy-5α-androstane (123 mg); mp 181-183 ° C; TLC R f (hexane: acetone 7: 3) = 0.31.
Una solución de 1,2-dibromoetileno (1,6 ml, 3,7 g, 19,71 milimoles) en THF seco (10 ml) se trató con n-BuLi (16,4 ml, 2,4M en THF, 39,4 milimoles) a -75ºC. Después de agitar la mezcla a -78ºC durante 0,25 horas, se añadió una solución de 17\beta-metoxi-5\beta-androsan-3-ona (2 g, 6,57 milimoles) en THF (20 ml) y la mezcla se agitó a -78ºC durante 15 minutos. El baño de enfriamiento se retiró a continuación y la mezcla se extinguió con solución de NH_{4}Cl (3 ml). Los disolventes se retiraron y el residuo se extrajo con EtOAc. La capa orgánica se lavó con agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el producto en bruto. Este producto en bruto se disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de sílice. La elución con mezcla de tolueno:acetona (95:5) daba 3\beta-etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano (1,70 g) como un sólido incoloro; pf 62-65ºC; TLC R_{f} (tolueno:acetona 95:5) = 0,23.A solution of 1,2-dibromoethylene (1.6 ml, 3.7 g, 19.71 mmol) in dry THF (10 ml) was treated with n-BuLi (16.4 ml, 2.4M in THF, 39.4 mmol) at -75 ° C. After stirring the mixture to -78 ° C for 0.25 hours, a solution of 17β-methoxy-5β-androsan-3-one (2 g, 6.57 mmol) in THF (20 ml) and the mixture was stirred at -78 ° C during 15 minutes. The cooling bath was then removed. and the mixture was quenched with NH4Cl solution (3 ml). The Solvents were removed and the residue was extracted with EtOAc. The layer Organic washed with water and brine. After drying over MgSO4 anhydrous, the solution was filtered and evaporated to give the raw product. This crude product was then dissolved. in a small amount of CH2Cl2 and poured into a silica gel column. Elution with toluene mixture: acetone (95: 5) gave 3β-ethynyl-3α-hydroxy-17β-methoxy-5β-androstane (1.70 g) as a colorless solid; mp 62-65 ° C; FTA R f (toluene: acetone 95: 5) = 0.23.
Una solución de 4-yodoacetofenona (112 mg, 0,45 milimoles) y 3\beta-etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano (150 mg, 0,45 milimoles) en trietilamina desgasificada seca (1 ml) se agitó bajo argón a 23ºC. Se añadieron cloruro de bis(trifenilfosfina)paladio (5 mg) y CuI (5 mg) y la mezcla se agitó a esta temperatura durante 45 minutos. Se añadió CH_{2}Cl_{2} (5 ml) y la mezcla se agitó a 23ºC durante 1 hora. La TLC mostraba 100% de conversión del material de partida y de ahí que el disolvente se retirara y el residuo se purificara mediante cromatografía en gel de sílice. La elución con hexano:EtOAc (7:3) daba 3\beta-(4'-acetilfeniletinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano (130 mg) como un sólido incoloro; pf 189-191ºC; TLC R_{f} (hexano:acetona 4:1) = 0,31.A solution of 4-iodoacetophenone (112 mg, 0.45 millimoles) and 3β-ethynyl-3α-hydroxy-17β-methoxy-5β-androstane (150 mg, 0.45 mmol) in dry degassed triethylamine (1 ml) stirred under argon at 23 ° C. Chloride was added bis (triphenylphosphine) palladium (5 mg) and CuI (5 mg) and the The mixture was stirred at this temperature for 45 minutes. Was added CH 2 Cl 2 (5 ml) and the mixture was stirred at 23 ° C for 1 hour. The FTA showed 100% conversion of the starting material and from there that the solvent is removed and the residue is purified by silica gel chromatography. Elution with hexane: EtOAc (7: 3) gave 3β- (4'-acetylphenylethynyl) -3α-hydroxy-17β-methoxy-5β-androstane (130 mg) as a colorless solid; mp 189-191 ° C; FTA R f (hexane: acetone 4: 1) = 0.31.
Una solución de 1,2-dibromoetileno (1,7 ml, 21 milimoles) en THF seco (25 ml) se trató con n-BuLi (16,8 ml, 2,5M en THF, 42 milimoles) a -65ºC. Después de agitar la mezcla a -70ºC durante 0,25 horas, se añadió una solución de 17\beta-metoxi-5\alpha-androsan-3-ona (2,128 g, 7 milimoles) en THF (22 ml) y la mezcla se agitó a -78ºC durante 30 minutos. El baño de enfriamiento se retiró a continuación y la mezcla se extinguió con solución de NH_{4}Cl (3 ml). Los disolventes se retiraron y el residuo se extrajo con EtOAc. La capa orgánica se lavó con agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el producto en bruto. Este producto en bruto se disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de sílice. La elución con mezcla de tolueno:acetona (95:5) daba 3\beta-etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano (100 mg) como un sólido incoloro; pf 138-145ºC; TLC R_{f} (hexano:acetona 7:3) = 0,45; y a continuación 3\alpha-etinil-3\beta-hidroxi-17\beta-metoxi-5\beta-androstano (1,6 g) como un sólido incoloro.A solution of 1,2-dibromoethylene (1.7 ml, 21 mmol) in THF dry (25 ml) was treated with n-BuLi (16.8 ml, 2.5M in THF, 42 millimoles) at -65 ° C. After stirring the mixture at -70 ° C for 0.25 hours, a solution of 17β-methoxy-5α-androsan-3-one (2,128 g, 7 mmol) in THF (22 ml) and the mixture was stirred at -78 ° C for 30 minutes The cooling bath was removed to then the mixture was quenched with NH4Cl solution (3 ml) The solvents were removed and the residue was extracted with EtOAc The organic layer was washed with water and brine. After Dry over anhydrous MgSO4, the solution was filtered and evaporated To give the raw product. This crude product was dissolved at then in a small amount of CH2Cl2 and it was poured on a column of silica gel. Elution with mixture of toluene: acetone (95: 5) gave 3β-ethynyl-3α-hydroxy-17β-methoxy-5β-androstane (100 mg) as a colorless solid; mp 138-145 ° C; FTA R f (hexane: acetone 7: 3) = 0.45; and then 3α-ethynyl-3β-hydroxy-17β-methoxy-5β-androstane (1.6 g) as a colorless solid.
Una solución de 1,2-dibromoetileno (0,9 ml, 2,0 g, 10,85 milimoles) en THF seco (10 ml) se trató con n-BuLi (9 ml, 2,4M en THF, 21,7 milimoles) a -75ºC. Después de agitar la mezcla a -78ºC durante 0,25 horas, se añadió una solución de 17\beta-metoxi-19-nor-5\beta-androsan-3-ona (1 g, 3,62 milimoles) en THF (20 ml) y la mezcla se agitó a -78ºC durante 20 minutos. El baño de enfriamiento se retiró a continuación y la mezcla se extinguió con solución de NH_{4}Cl (3 ml). Los disolventes se retiraron y el residuo se extrajo con EtOAc. La capa orgánica se lavó con agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el producto en bruto. Este producto en bruto se disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de sílice. La elución con mezcla de tolueno:acetona (98:2) daba 3\beta-etinil-3\alpha-hidroxi-17\beta-metoxi-19-nor-5\beta-androstano (750 mg) como un sólido incoloro; pf 152-154ºC; TLC R_{f} (hexano:acetona 7:3) = 0,58.A solution of 1,2-dibromoethylene (0.9 ml, 2.0 g, 10.85 mmol) in dry THF (10 ml) it was treated with n-BuLi (9 ml, 2.4M in THF, 21.7 mmol) at -75 ° C. After stirring the mixture to -78 ° C for 0.25 hours, a solution of 17β-methoxy-19-nor-5β-androsan-3-one (1 g, 3.62 mmol) in THF (20 ml) and the mixture was stirred at -78 ° C during 20 minutes. The cooling bath was removed to then the mixture was quenched with NH4Cl solution (3 ml) The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water and brine. After drying over anhydrous MgSO4, the solution was filtered and evaporated to Give the raw product. This crude product was dissolved at then in a small amount of CH2Cl2 and it poured into a column of silica gel. Elution with mixture of toluene: acetone (98: 2) gave 3β-ethynyl-3α-hydroxy-17β-methoxy-19-nor-5β-androstane (750 mg) as a colorless solid; mp 152-154 ° C; FTA R f (hexane: acetone 7: 3) = 0.58.
Una solución de 4-yodoacetofenona (117 mg, 0,47 milimoles) y 3\beta-etinil-3\alpha-hidroxi-17\beta-metoxi-19-nor-5\beta-androstano (150 mg, 0,47 milimoles) en trietilamina desgasificada seca (1 ml) se agitó bajo argón a 23ºC. Se añadieron cloruro de bis(trifenilfosfina)paladio (5 mg) y CuI (5 mg) y la mezcla se agitó a esta temperatura durante 45 minutos. Se añadió CH_{2}Cl_{2} (5 ml) y la mezcla se agitó a 23ºC durante 1 hora. La TLC mostraba 100% de conversión del material de partida, de ahí que la solución se retirara y el residuo se purificara mediante cromatografía sobre gel de sílice. La elución con tolueno:acetona (95:5) daba 3\beta-(4'-acetilfeniletinil)-3\alpha-hidroxi-17\beta-metoxi-19-nor-5\beta-androstano (105 mg) como un sólido incoloro; pf 148-150ºC; TLC R_{f} (hexano:acetona 4:1) = 0,52.A solution of 4-iodoacetophenone (117 mg, 0.47 mmol) and 3β-ethynyl-3α-hydroxy-17β-methoxy-19-nor-5β-androstane (150 mg, 0.47 mmol) in dry degassed triethylamine (1 ml) stirred under argon at 23 ° C. Chloride was added bis (triphenylphosphine) palladium (5 mg) and CuI (5 mg) and the The mixture was stirred at this temperature for 45 minutes. Was added CH 2 Cl 2 (5 ml) and the mixture was stirred at 23 ° C for 1 hour. The FTA showed 100% conversion of the starting material, hence that the solution be removed and the residue purified by silica gel chromatography. Elution with toluene: acetone (95: 5) gave 3β- (4'-acetylphenylethynyl) -3α-hydroxy-17β-methoxy-19-nor-5β-androstane (105 mg) as a colorless solid; mp 148-150 ° C; FTA R f (hexane: acetone 4: 1) = 0.52.
Una solución de 17\beta-metoxi-19-nor-5\beta-androstan-3-ona (300 mg, 1,08 milimoles) en THF seco (5 ml) se trató con trifluorometiltrimetilsilano (5 ml, 0,5M en THF, 2,5 milimoles) y TBAF (5 mg) a 0ºC. Después de agitar la mezcla a 23ºC durante 2 horas, la mezcla se volvió a enfriar hasta 0ºC. Se añadió una solución de TBAF (1M en THF, 3,5 ml, 3,5 milimoles). La mezcla se agitó a temperatura ambiente durante 10 minutos y a continuación se extinguió con solución de NH_{4}Cl (5 ml). Los disolventes se retiraron y el residuo se extrajo con EtOAc. La capa orgánica se lavó con agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el producto en bruto. Este producto en bruto se disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de sílice. La elución con mezcla de hexano:acetona (9:1) daba 3\alpha-hidroxi-17\beta-metoxi-3\beta-trifluorometil-19-nor-5\beta-androstano (210 mg); pf 40-42ºC; TLC R_{f} (hexano:acetona 7:3) = 0,66.A solution of 17β-methoxy-19-nor-5β-androstan-3-one (300 mg, 1.08 mmol) in dry THF (5 ml) was treated with trifluoromethyltrimethylsilane (5 ml, 0.5M in THF, 2.5 millimoles) and TBAF (5 mg) at 0 ° C. After stirring the mixture at 23 ° C for 2 hours, the mixture was cooled again to 0 ° C. Added one TBAF solution (1M in THF, 3.5 ml, 3.5 mmol). The mixture is stirred at room temperature for 10 minutes and then quenched with NH4Cl solution (5 ml). The solvents are removed and the residue was extracted with EtOAc. The organic layer is washed with water and brine. After drying over MgSO4 anhydrous, the solution was filtered and evaporated to give the product in stupid. This crude product was then dissolved in a small amount of CH2Cl2 and was poured into a column of Silica gel. Elution with hexane mixture: acetone (9: 1) gave 3α-hydroxy-17β-methoxy-3β-trifluoromethyl-19-nor-5β-androstane (210 mg); mp 40-42 ° C; TLC R f (hexane: acetone 7: 3) = 0.66.
Ejemplo de Referencia 19Reference Example 19
Una solución de yoduro de trimetilsulfoxonio (2,42 g, 11 milimoles) y KOt-Bu (1,12 g, 10 milimoles) en THF seco (40 ml) se sometió a reflujo durante 2 horas. Después de enfriar hasta temperatura ambiente, se añadió 17\beta-metoxi- 5\alpha-androstan-3-ona (2,432 g, 8 milimoles) y la mezcla se agitó a esta temperatura durante 3 horas. Se extinguió a continuación con agua (5 ml). Los disolventes se retiraron y el residuo se extrajo con EtOAc. La capa orgánica se lavó con HCl diluido, agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el 3(R)-espiro-2'-oxirano-17\beta-metoxi-5\alpha-androstano en bruto (2,5 g). Este producto en bruto se usó a continuación como tal para la siguiente etapa.A solution of trimethylsulfoxonium iodide (2.42 g, 11 millimoles) and KOt-Bu (1.12 g, 10 millimoles) in dry THF (40 ml) was refluxed for 2 hours. After cooling to room temperature, it was added 17? -Methoxy- 5α-androstan-3-one (2,432 g, 8 mmol) and the mixture was stirred at this temperature during 3 hours. It was then quenched with water (5 ml). The Solvents were removed and the residue was extracted with EtOAc. The layer Organic was washed with dilute HCl, water and brine. After drying over anhydrous MgSO4, the solution was filtered and evaporated to Give the 3 (R) -spiro-2'-oxirane-17β-methoxy-5α-androstane raw (2.5 g). This raw product was used below. As such for the next stage.
Una solución de 3(R)-espiro-2'-oxirano-17\beta-metoxi-5\alpha-androstano en bruto (318 mg, 1 milimol) y acetiluro de litio y EDA (95%, 486 mg, 5 milimoles) en DMSO (10 ml) se agitó a temperatura ambiente durante 15 horas. Se extinguió a continuación con agua (30 ml) y se extrajo con EtOAc. La capa orgánica se lavó con agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el producto. Este producto en bruto se disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de sílice. La elución con mezcla de hexano:acetona (8:2) daba 3\alpha-hidroxi-17\beta-metoxi-3\beta-(2-propinil)-5\beta-androstano (200 mg); pf 145-150ºC; TLC R_{f} (hexano:acetona 7:3) = 0,6.A solution of 3 (R) -spiro-2'-oxirane-17β-methoxy-5α-androstane crude (318 mg, 1 millimol) and lithium acetylide and EDA (95%, 486 mg, 5 mmol) in DMSO (10 ml) was stirred at room temperature for 15 hours It was then quenched with water (30 ml) and extracted with EtOAc. The organic layer was washed with water and brine. After drying over anhydrous MgSO4, the solution was filtered and It was evaporated to give the product. This raw product dissolved then in a small amount of CH2Cl2 and it poured into a column of silica gel. Elution with mixture of hexane: acetone (8: 2) gave 3α-hydroxy-17β-methoxy-3β- (2-propynyl) -5β-androstane (200 mg); mp 145-150 ° C; TLC R f (hexane: acetone 7: 3) = 0.6.
Una solución de 3(R)-espiro-2'-oxirano-17\beta-metoxi-5\alpha-androstano en bruto (318 mg, 1 milimol) y sodio (29 mg, 1,3 milimoles) en MeOH (10 ml) se sometió a reflujo durante 2,5 horas. Se extinguió a continuación con agua (1 ml). Los disolventes se retiraron y el residuo se extrajo con EtOAc. La capa orgánica se lavó con agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el producto en bruto. Este producto en bruto se disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de sílice. La elución con mezcla de hexano:acetona (8:2) daba 3\alpha-hidroxi-17\beta-metoxi-3\beta-metoximetil-5\beta-androstano (230 mg); pf 93-99ºC; TLC R_{f} (hexano:acetona 7:3) = 0,56.A solution of 3 (R) -spiro-2'-oxirane-17β-methoxy-5α-androstane crude (318 mg, 1 mmol) and sodium (29 mg, 1.3 mmol) in MeOH (10 ml) was refluxed for 2.5 hours. Became extinct at then with water (1 ml). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water and brine. After drying over anhydrous MgSO4, the solution is filtered and evaporated to give the crude product. This product in crude was then dissolved in a small amount of CH 2 Cl 2 and was poured onto a silica gel column. The elution with hexane mixture: acetone (8: 2) gave 3α-hydroxy-17β-methoxy-3β-methoxymethyl-5β-androstane (230 mg); mp 93-99 ° C; TLC R f (hexane: acetone 7: 3) = 0.56.
Una solución de 3(R)-espiro-2'-oxirano-17\beta-metoxi-5\alpha-androstano en bruto (318 mg, 1 milimol), cloruro de tetrametilamonio (166 mg, 1,5 milimoles) y ácido acético (0,5 ml) en DMF (10 ml) se agitó a 90-95ºC durante 2,5 horas. Se enfrió hasta temperatura ambiente y a continuación se extinguió con agua (25 ml). Después de neutralizar con NaOH 2N, la mezcla se extrajo con EtOAc. La capa orgánica se lavó con agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el producto en bruto. Este producto en bruto se disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de sílice. La elución con mezcla de hexano:acetona (95:5) daba 3\beta-clorometil-3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano (138 mg); pf 138-145ºC; TLC R_{f} (hexano:acetona 8:2) = 0,26.A solution of 3 (R) -spiro-2'-oxirane-17β-methoxy-5α-androstane crude (318 mg, 1 millimol), tetramethylammonium chloride (166 mg, 1.5 millimoles) and acetic acid (0.5 ml) in DMF (10 ml) was stirred at 90-95 ° C for 2.5 hours. It cooled down room temperature and then extinguished with water (25 ml) After neutralizing with 2N NaOH, the mixture was extracted with EtOAc The organic layer was washed with water and brine. After Dry over anhydrous MgSO4, the solution was filtered and evaporated To give the raw product. This crude product was dissolved at then in a small amount of CH2Cl2 and it poured into a column of silica gel. Elution with mixture of hexane: acetone (95: 5) gave 3β-chloromethyl-3α-hydroxy-17β-methoxy-5α-androstane (138 mg); mp 138-145 ° C; TLC R f (hexane: acetone 8: 2) = 0.26.
Una solución de yoduro de trimetilsulfonio (632 mg, 3,1 milimoles) en THF seco (10 ml) se trató con n-BuLi (2,5 M en THF, 3 milimoles, 1,2 ml) a -5ºC. Después de agitar la mezcla a 0ºC durante 0,5 horas, se añadió una solución de 3(R)-espiro-2'-oxirano-17\beta-metoxi-5\alpha-androstano (318 mg, 1 milimol) en THF (10 ml). El baño de enfriamiento se retiró y la mezcla se agitó a temperatura ambiente durante 2 horas. Se extinguió a continuación con solución de NH_{4}Cl (2 ml). Los disolventes se retiraron y el residuo se extrajo con EtOAc. La capa orgánica se lavó con agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el producto en bruto. Este producto en bruto se disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de sílice. La elución con mezcla de hexano:acetona (7:3) daba 3\beta-etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano (220 mg) como un sólido incoloro; pf 104-111ºC; TLC R_{f} (hexano:acetona 7:3) = 0,5.A solution of trimethylsulfonium iodide (632 mg, 3.1 mmol) in dry THF (10 ml) was treated with n-BuLi (2.5 M in THF, 3 mmol, 1.2 ml) at -5 ° C. After stirring the mixture at 0 ° C for 0.5 hours, a solution of 3 (R) -spiro-2'-oxirane-17β-methoxy-5α-androstane (318 mg, 1 millimol) in THF (10 ml). The cooling bath is removed and the mixture was stirred at room temperature for 2 hours. It was then quenched with NH4Cl solution (2 ml). The Solvents were removed and the residue was extracted with EtOAc. The layer Organic washed with water and brine. After drying over MgSO4 anhydrous, the solution was filtered and evaporated to give the raw product. This crude product was dissolved at then in a small amount of CH2Cl2 and it poured into a column of silica gel. Elution with mixture of hexane: acetone (7: 3) gave 3β-ethynyl-3α-hydroxy-17β-methoxy-5β-androstane (220 mg) as a colorless solid; mp 104-111 ° C; FTA R f (hexane: acetone 7: 3) = 0.5.
Una solución de 17-dimetilacetal de 3\alpha-hidroxi-2\beta-isopropoxi-5\alpha-androstan-17-ona (preparado mediante la apertura del epóxido de 2\alpha,3\alpha-epoxi-5\alpha-androstan-17-ona con isopropóxido, seguido por cetalización de la 17-ona) (1490 mg, 1,25 milimoles) en THF seco (15 ml) se trató con LAH (48 mg, 1,33 milimoles) y AlCl_{3} (332 mg, 2,5 milimoles) a -30ºC. Después de agitar la mezcla a 23ºC durante 1 hora, se extinguió con solución de NH_{4}Cl (2 ml). Los disolventes se retiraron y el residuo se extrajo con EtOAc. La capa orgánica se lavó con HCl diluido, agua y salmuera. Después de secar sobre MgSO_{4} anhidro, la solución se filtró y se evaporó para dar el producto en bruto. Este producto en bruto se disolvió a continuación en una pequeña cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de sílice. La elución con mezcla de hexano:acetona (9:1) daba 3\alpha-hidroxi-2\beta-isopropoxi-17\beta-metoxi-5\alpha-androstano (43 mg) como una espuma; TLC R_{f} (hexano:acetona 7:3) = 0,41.A solution of 17-dimethylacetal from 3α-hydroxy-2β-isopropoxy-5α-androstan-17-one (prepared by opening the epoxide of 2α, 3α-epoxy-5α-androstan-17-one with isopropoxide, followed by ketalization of the 17-one) (1490 mg, 1.25 millimoles) in dry THF (15 ml) was treated with LAH (48 mg, 1.33 mmol) and AlCl 3 (332 mg, 2.5 millimoles) at -30 ° C. After stirring the mixture at 23 ° C for 1 hour, quenched with NH 4 Cl solution (2 ml). The Solvents were removed and the residue was extracted with EtOAc. The layer Organic was washed with dilute HCl, water and brine. After drying over anhydrous MgSO4, the solution was filtered and evaporated to Give the raw product. This crude product was dissolved at then in a small amount of CH2Cl2 and it poured into a column of silica gel. Elution with mixture of hexane: acetone (9: 1) gave 3α-hydroxy-2β-isopropoxy-17β-methoxy-5α-androstane (43 mg) as a foam; TLC R f (hexane: acetone 7: 3) = 0.41.
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Ejemplo de Referencia 25Reference Example 25
Una solución de 21-bromo-3\alpha-hidroxi-3\beta-(4-hidroxibutinil)-5\beta-pregnan-20-ona (230 mg, 0,494 milimoles), 4-mercaptopiridina al 90% (77 mg, 0,618 milimoles) y trietilamina (86 \mul, 0,618 milimoles) en 10 ml de acetonitrilo se agitó a temperatura ambiente durante 3 horas. La mezcla se sometió a reparto entre EtOAc y agua. La capa orgánica se lavó con NaCl acuoso saturado, se secó con Na_{2}SO_{4} y se concentró a vacío. El residuo en bruto se sometió a cromatografía en columna de desarrollo rápido. La elución con acetona 35% \rightarrow 50% en CH_{2}Cl_{2} daba 3\alpha-hidroxi-3\beta-(4-hidroxibutinil)-21-(pirid-4-iltio)-5\beta-pregnan-20-ona (196 mg) como una espuma amarilla. TLC R_{f} (acetona:CH_{2}Cl_{2} 45:55) = 0,36.A solution of 21-bromo-3α-hydroxy-3β- (4-hydroxybutynyl) -5β-pregnan-20-one (230 mg, 0.494 mmol), 4-mercaptopyridine at 90% (77 mg, 0.618 mmol) and triethylamine (86 µL, 0.618 millimoles) in 10 ml of acetonitrile was stirred at room temperature during 3 hours. The mixture was partitioned between EtOAc and water. The organic layer was washed with saturated aqueous NaCl, dried with Na2SO4 and concentrated in vacuo. The raw waste is underwent rapid development column chromatography. Elution with 35% acetone 50% in CH 2 Cl 2 gave 3α-hydroxy-3β- (4-hydroxybutynyl) -21- (pyrid-4-ylthio) -5β-pregnan-20-one (196 mg) as a yellow foam. TLC R f (acetone: CH 2 Cl 2 45:55) = 0.36.
Se prepararon de forma similar:They were prepared similarly:
3\alpha-hidroxi-21-(pirid-4-iltio)-5\beta-pregnan-20-ona; pf 193-195ºC; TLC R_{f} (hexano:EtOAc 1:1) = 0,11;3α-hydroxy-21- (pyrid-4-ylthio) -5β-pregnan-20-one; mp 193-195 ° C; TLC R f (hexane: EtOAc 1: 1) = 0.11;
3\alpha-hidroxi-21-(pirid-4-iltio)-5\alpha-pregnan-20-ona; pf 154-156ºC; TLC R_{f} (CH_{2}Cl_{2}:acetona 4:1) = 0,18;3α-hydroxy-21- (pyrid-4-ylthio) -5α-pregnan-20-one; mp 154-156 ° C; TLC R f (CH 2 Cl 2: acetone 4: 1) = 0.18;
3\alpha-hidroxi-3\beta-metoximetil-21-(pirid-4-iltio)-5\alpha-pregnan-20-ona;3α-hydroxy-3β-methoxymethyl-21- (pyrid-4-ylthio) -5α-pregnan-20-one;
21-(4'-aminofeniltio)-3\alpha-hidroxi-3\beta-metoximetil-5\alpha-pregnan-20-ona; pf 150-156ºC; TLC R_{f} (hexano:EtOAc 3:1) = 0,045;21- (4'-aminophenylthio) -3α-hydroxy-3β-methoxymethyl-5α-pregnan-20-one; mp 150-156 ° C; TLC R f (hexane: EtOAc 3: 1) = 0.045;
3\alpha-hidroxi-3\beta-metoximetil-21-(4'-nitrofeniltio)-5\alpha-pregnan-20-ona; TLC R_{f} (hexano:EtOAc 3:1) = 0,17;3α-hydroxy-3β-methoxymethyl-21- (4'-nitrophenylthio) -5α-pregnan-20-one; TLC Rf (hexane: EtOAc 3: 1) = 0.17;
21-(4'-fluorofeniltio)-3\alpha-hidroxi-3\beta-metoximetil-5\alpha-pregnan-20-ona; TLC R_{f} (hexano:acetona 85:15) = 0,25;21- (4'-fluorophenylthio) -3α-hydroxy-3β-methoxymethyl-5α-pregnan-20-one; TLC R f (hexane: acetone 85:15) = 0.25;
3\beta-etinil-3\alpha-hidroxi-21-(pirid-4-iltio)-5\alpha-pregnan-20-ona; TLC R_{f} (hexano:EtOAc 1:1) = 0,26; y3β-ethynyl-3α-hydroxy-21- (pyrid-4-ylthio) -5α-pregnan-20-one; TLC R f (hexane: EtOAc 1: 1) = 0.26; Y
3\beta-(4'-acetilfenil)etinil-3\alpha-hidroxi-21-(pirid-4-iltio)-5\beta-pregnan-20-ona; TLC R_{f} (hexano:EtOAc 2:1) = 0,15.3β- (4'-acetylphenyl) ethynyl-3α-hydroxy-21- (pyrid-4-ylthio) -5β-pregnan-20-one; TLC R f (hexane: EtOAc 2: 1) = 0.15.
Ejemplo de Referencia 26Reference Example 26
Una solución de 3\alpha-hidroxi-21-(pirid-4-iltio)-5\beta-pregnan-20-ona (62 mg,0,145 milimoles) y 1 ml de yoduro de metilo en 5 ml de EtOAc se calentó hasta reflujo durante unas pocas horas hasta una reacción completa por TLC. La mezcla se enfrió a continuación hasta temperatura ambiente y se concentró a vacío hasta un residuo en bruto. El residuo se trituró con éter y se secó bajo vacío par dar N-metilyoduro de 3\alpha-hidroxi-21-(pirid-4-iltio)-5\beta-pregnan-20-ona (70 mg) como un sólido naranja.A solution of 3α-hydroxy-21- (pyrid-4-ylthio) -5β-pregnan-20-one (62 mg, 0.145 mmol) and 1 ml of methyl iodide in 5 ml of EtOAc heated to reflux for a few hours until a complete reaction by TLC. The mixture was then cooled until room temperature and concentrated in vacuo to a residue in stupid. The residue was triturated with ether and dried under vacuum to give N-methyliodide 3α-hydroxy-21- (pyrid-4-ylthio) -5β-pregnan-20-one (70 mg) as an orange solid.
Ejemplo de Referencia 27Reference Example 27
Una solución de 3\alpha-hidroxi-21-(pirid-4-iltio)-5\alpha-pregnan-20-ona (29 mg,0,068 milimoles) y 100 \mul de yoduro de metilo en 5 ml de THF se calentó hasta reflujo. Después de 15 minutos, precipitó un sólido y el reflujo se continuó durante unas pocas horas. La mezcla se enfrió hasta temperatura ambiente y el yoduro de metilo en exceso se dejó evaporar. El sólido se filtró a continuación, lavando con THF frío, dando como resultado N-metilyoduro de 3\alpha-hidroxi-21-(pirid-4-iltio)-5\alpha-pregnan-20-ona (26 mg) como un sólido naranja claro.A solution of 3α-hydroxy-21- (pyrid-4-ylthio) -5α-pregnan-20-one (29 mg, 0.068 mmol) and 100 µl of methyl iodide in 5 ml of THF was heated to reflux. After 15 minutes, precipitated a solid and reflux was continued for a few hours. Mix cooled to room temperature and methyl iodide in excess was allowed to evaporate. The solid was then filtered, washing with cold THF, resulting in N-methyliodide 3α-hydroxy-21- (pyrid-4-ylthio) -5α-pregnan-20-one (26 mg) as a light orange solid.
Ejemplo de Referencia 28Reference Example 28
Una solución de 3\alpha-hidroxi-2\beta-propoxi-21-(pirid-4-iltio)-5\alpha-pregnan-20-ona (50 mg,0,103 milimoles) y 130 \mul de yoduro de metilo en 5 ml de THF se calentó hasta reflujo durante unas pocas horas hasta una reacción completa por TLC. La mezcla se enfrió a continuación hasta temperatura ambiente y se concentró a vacío dando como resultado N-metilyoduro de 3\alpha-hidroxi-2\beta-propoxi-21-(pirid-4-iltio)-5\alpha-pregnan-20-ona (64 mg) como un sólido amarillo claro.A solution of 3α-hydroxy-2β-propoxy-21- (pyrid-4-ylthio) -5α-pregnan-20-one (50 mg, 0.103 mmol) and 130 µl of methyl iodide in 5 ml of THF was heated to reflux for a few hours until a complete reaction by TLC. The mixture was then cooled until room temperature and concentrated in vacuo resulting in N-methyliodide 3α-hydroxy-2β-propoxy-21- (pyrid-4-ylthio) -5α-pregnan-20-one (64 mg) as a light yellow solid.
Se prepararon de forma similar:They were prepared similarly:
sal de yoduro de 3\alpha-hidroxi-3\beta-metil-21-(4'-trimetilamoniofenoxi)-5\alpha-pregnan-20-ona;iodide salt of 3α-hydroxy-3β-methyl-21- (4'-trimethylammoniophenoxy) -5α-pregnan-20-one;
sal de yoduro de 3\alpha-hidroxi-2\beta-propoxi-21-(4'-N,N,N-trimetilamoniofenoxi)-5\alpha-pregnan-20-ona; yiodide salt of 3α-hydroxy-2β-propoxy-21- (4'-N, N, N-trimethylammoniophenoxy) -5α-pregnan-20-one; Y
N-metilyoduro de 3\alpha-hidroxi-3\beta-metil-21-(quinolin-6-iloxi)-5\alpha-pregnan-20-ona.N-methyliodide 3α-hydroxy-3β-methyl-21- (quinolin-6-yloxy) -5α-pregnan-20-one.
Ejemplo de Referencia 29Reference Example 29
Una solución de 21-bromo-3\beta-etinil-3\alpha-hidroxi-5\beta-pregnan-20-ona (150 mg, 0,356 milimoles), 2-mercaptoetanol (31 \mul, 0,445 milimoles) y trietilamina (62 \mul, 0,445 milimoles) en 5 ml de THF se agitó a temperatura ambiente durante la noche. La mezcla se sometió a reparto entre EtOAc y agua. La capa orgánica se lavó con NaCl acuoso saturado, se secó con Na_{2}SO_{4} y se concentró a vacío dando como resultado 3\beta-etinil-3\alpha-hidroxi-21-hidroxietiltio-5\beta-pregnan-20-ona (141 mg) como un sólido blanco; pf 122-126ºC; TLC R_{f} (hexano:acetona 3:1) = 0,11.A solution of 21-bromo-3β-ethynyl-3α-hydroxy-5β-pregnan-20-one (150 mg, 0.356 mmol), 2-mercaptoethanol (31 µ, 0.445 mmol) and triethylamine (62 µ, 0.445 millimoles) in 5 ml of THF was stirred at room temperature for the night. The mixture was partitioned between EtOAc and water. The Organic layer was washed with saturated aqueous NaCl, dried with Na 2 SO 4 and concentrated in vacuo resulting in 3β-ethynyl-3α-hydroxy-21-hydroxyethylthio-5β-pregnan-20-one (141 mg) as a white solid; mp 122-126 ° C; FTA R f (hexane: acetone 3: 1) = 0.11.
Se prepararon de forma similar:They were prepared similarly:
3\beta-etinil-3\alpha-hidroxi-21-hidroxipropiltio-5\beta-pregnan-20-ona; TLC R_{f} (hexano:acetona 3:1) = 0,12;3β-ethynyl-3α-hydroxy-21-hydroxypropylthio-5β-pregnan-20-one; TLC R f (hexane: acetone 3: 1) = 0.12;
3\alpha-hidroxi-21-hidroxipropiltio-2\beta-propoxi-5\alpha-pregnan-20-ona; pf 133-136ºC; TLC R_{f} (hexano:acetona 3:1) = 0,175; y3α-hydroxy-21-hydroxypropylthio-2β-propoxy-5α-pregnan-20-one; mp 133-136 ° C; TLC R f (hexane: acetone 3: 1) = 0.175; Y
3\alpha-hidroxi-21-hidroxietiltio-5\beta-pregnan-20-ona; pf 150-152ºC.3α-hydroxy-21-hydroxyethylthio-5β-pregnan-20-one; mp 150-152 ° C.
Ejemplo de Referencia 30Reference Example 30
Una solución de 21-bromo-3\beta-etinil-3\alpha-hidroxi-5\beta-pregnan-20-ona (150 mg, 0,356 milimoles), ácido mercaptoacético (31 \mul, 0,445 milimoles) y trietilamina (124 \mul, 0,89 milimoles) en 5 ml de DMF se agitó a temperatura ambiente durante unas pocas horas. La mezcla se sometió a reparto entre EtOAc y HCl 1N. La capa orgánica se lavó con agua, NaCl acuoso saturado, se secó con Na_{2}SO_{4} y se concentró a vacío hasta un residuo. El residuo se disolvió en 5 ml de CH_{2}Cl_{2} y se añadió un equivalente de bicarbonato sódico en 1 ml de agua. La mezcla se agitó durante 30 minutos y a continuación se concentró hasta sequedad bajo alto vacío dando como resultado sal sódica de 3\beta-etinil-3\alpha-hidroxi-21-tioetanoato-5\beta-pregnan-20-ona (120 mg) como un sólido blanco; Desc. > 120ºC.A solution of 21-bromo-3β-ethynyl-3α-hydroxy-5β-pregnan-20-one (150 mg, 0.356 mmol), mercaptoacetic acid (31 µL, 0.445 millimoles) and triethylamine (124 µL, 0.89 mmol) in 5 ml of DMF was stirred at room temperature for a few hours. The The mixture was partitioned between EtOAc and 1N HCl. Organic layer washed with water, saturated aqueous NaCl, dried with Na2SO4 and concentrated in vacuo to a residue. The residue it was dissolved in 5 ml of CH2Cl2 and an equivalent was added of sodium bicarbonate in 1 ml of water. The mixture was stirred for 30 minutes and then concentrated to dryness under high vacuum resulting in sodium salt of 3β-ethynyl-3α-hydroxy-21-thioethanoate-5β-pregnan-20-one (120 mg) as a white solid; Desc. > 120 ° C.
Se prepararon de forma similar:They were prepared similarly:
sal sódica de 3\beta-etinil-3\alpha-hidroxi-21-tiopropanoato-5\beta-pregnan-20-ona;sodium salt of 3β-ethynyl-3α-hydroxy-21-thiopropanoate-5β-pregnan-20-one;
sal sódica de
3\beta-etinil-3\alpha-hidroxi-21-tioetanosulfonato-5\beta-pregnan-20-ona;
desc. > 85ºC; TLC R_{f} (cloroformo:
metanol 4:1) =
0,25;3β-ethynyl-3α-hydroxy-21-thioethanesulfonate-5β-pregnan-20-one sodium salt; off > 85 ° C; TLC R f (chloroform:
methanol 4: 1) = 0.25;
sal sódica de 3\beta-etinil-3\alpha-hidroxi-21-tiopropanosulfonato-5\beta-pregnan-20-ona; TLC R_{f} (cloroformo:metanol 4:1) = 0,21; ysodium salt of 3β-ethynyl-3α-hydroxy-21-thiopropanesulfonate-5β-pregnan-20-one; TLC Rf (chloroform: methanol 4: 1) = 0.21; Y
sal sódica de 3\alpha-hidroxi-2\beta-propoxi-21-tiopropanosulfonato-5\alpha-pregnan-20-ona; TLC R_{f} (cloroformo:metanol 85:15) = 0,22.sodium salt of 3α-hydroxy-2β-propoxy-21-thiopropanesulfonate-5α-pregnan-20-one; TLC R f (chloroform: methanol 85:15) = 0.22.
Ejemplo de Referencia 31Reference Example 31
Una solución de 3\beta-etinil-3\alpha-hidroxi-21-hidroxietiltio-5\beta-pregnan-20-ona (140 mg, 0,335 milimoles), complejo de trióxido de azufre-trimetilamina (100 mg, 0,736 milimoles) y complejo de trióxido de azufre-piridina (50 mg) en 4 ml de cloroformo se agitó a temperatura ambiente durante la noche. El sólido se filtró y el filtrado se concentró hasta un volumen pequeño. El residuo se sometió a cromatografía en columna de desarrollo rápido. La elución con cloroformo:metanol 85:15 daba como resultado sal trimetilamónica de 3\beta-etinil-3\alpha-hidroxi-21-tioetanosulfato-5\beta-pregnan-20-ona (69 mg) como un sólido; Desc. > 120ºC.A solution of 3β-ethynyl-3α-hydroxy-21-hydroxyethylthio-5β-pregnan-20-one (140 mg, 0.335 mmol), trioxide complex sulfur-trimethylamine (100 mg, 0.736 mmol) and sulfur trioxide-pyridine complex (50 mg) in 4 ml of chloroform was stirred at room temperature during night. The solid was filtered and the filtrate was concentrated to a small volume The residue was subjected to column chromatography. of rapid development. Elution with chloroform: methanol 85:15 gave as a result trimethyl ammonium salt of 3β-ethynyl-3α-hydroxy-21-thioethanesulfate-5β-pregnan-20-one (69 mg) as a solid; Desc. > 120 ° C.
Ejemplo de Referencia 32Reference Example 32
Una solución de 3\beta-etinil-3\alpha-hidroxi-21-hidroxipropiltio-5\beta-pregnan-20-ona (50 mg, 0,115 milimoles) y complejo de trióxido de azufre-trimetilamina (19 mg, 0,139 milimoles) en 0,5 ml de piridina se agitó a temperatura ambiente durante la noche. La mezcla se diluyó con cloroformo y se lavó con HCl 2N, NaCl acuoso saturado, se secó con Na_{2}SO_{4} y se concentró a vacío hasta un residuo en bruto. El residuo se sometió a cromatografía en columna de desarrollo rápido. La elución con cloroformo:metanol 85:15 daba como resultado sal sódica de 3\beta-etinil-3\alpha-hidroxi-21-tiopropanosulfato-5\beta-pregnan-20-ona (20 mg) como un sólido; TLC R_{f} (cloroformo:metanol 85:15) = 0,12.A solution of 3β-ethynyl-3α-hydroxy-21-hydroxypropylthio-5β-pregnan-20-one (50 mg, 0.115 mmol) and trioxide complex sulfur-trimethylamine (19 mg, 0.139 mmol) at 0.5 ml of pyridine was stirred at room temperature overnight. The mixture was diluted with chloroform and washed with 2N HCl, aqueous NaCl saturated, dried with Na2SO4 and concentrated in vacuo to a raw waste. The residue was subjected to chromatography in rapid development column. Elution with chloroform: methanol 85:15 resulted in sodium salt of 3β-ethynyl-3α-hydroxy-21-thiopropanesulfate-5β-pregnan-20-one (20 mg) as a solid; TLC R f (chloroform: methanol 85:15) = 0.12.
Se preparó de forma similar sal sódica de 3\alpha-hidroxi-2\beta-propoxi-21-sulfonilpropanosulfato-5\alpha-pregnan-20-ona; TLC R_{f} (cloroformo:metanol 85:15) = 0,15.Sodium salt of similarly prepared 3α-hydroxy-2β-propoxy-21-sulfonylpropanesulfate-5α-pregnan-20-one; TLC R f (chloroform: methanol 85:15) = 0.15.
Ejemplo de Referencia 33Reference Example 33
Una suspensión de 3\beta-etinil-3\alpha-hidroxi-21-hidroxipropiltio-5\beta-pregnan-20-ona (90 mg, 0,208 milimoles) y peryodato sódico (\sim200 mg en 0,5 ml de agua) en metanol:THF 3:1 se agitó desde 0ºC hasta temperatura ambiente durante la noche. La mezcla se concentró hasta un pequeño volumen y se sometió a reparto entre EtOAc y agua. La capa orgánica se lavó con NaCl acuoso saturado, se secó con Na_{2}SO_{4} y se concentró a vacío dando como resultado 3\beta-etinil-3\alpha-hidroxi-21-hidroxipropilsulfinil-5\beta-pregnan-20-ona (83 mg) como una espuma; TLC R_{f} (hexano:acetona 2:1) = 0,035.A suspension of 3β-ethynyl-3α-hydroxy-21-hydroxypropylthio-5β-pregnan-20-one (90 mg, 0.208 mmol) and sodium periodate (~ 200 mg in 0.5 ml of water) in methanol: THF 3: 1 was stirred from 0 ° C to temperature overnight atmosphere. The mixture was concentrated to a small volume and was partitioned between EtOAc and water. Organic layer washed with saturated aqueous NaCl, dried with Na2SO4 and dried concentrated under vacuum resulting in 3β-ethynyl-3α-hydroxy-21-hydroxypropylsulfinyl-5β-pregnan-20-one (83 mg) as a foam; TLC R f (hexane: acetone 2: 1) = 0.035.
Se preparó de forma similar sal sódica de 3\alpha-hidroxi-2\beta-propoxi-21-sulfinilpropano-sulfonato-5\alpha-pregnan-20-ona.Sodium salt of similarly prepared 3α-hydroxy-2β-propoxy-21-sulfinylpropane-sulfonate-5α-pregnan-20-one.
Ejemplo de Referencia 34Reference Example 3. 4
Una solución de 3\beta-etinil-3\alpha-hidroxi-21-hidroxipropilsulfinil-5\beta-pregnan-20-ona (65 mg, 0,145 milimoles), mCPBA al 57%-86% (42 mg) y una espátula de bicarbonato sódico en 5 ml de CH_{2}Cl_{2} se agitó desde 0ºC hasta temperatura ambiente durante la noche. La mezcla se sometió a reparto entre CH_{2}Cl_{2} y bicarbonato sódico acuoso. La capa orgánica se lavó con NaCl acuoso saturado, se secó con Na_{2}SO_{4} y se concentró a vacío hasta sequedad dando como resultado 3\beta-etinil-3\alpha-hidroxi-21-hidroxipropilsulfonil-5\beta-pregnan-20-ona (66 mg) como un sólido blanco; TLC R_{f} (CH_{2}Cl_{2}:acetona 1:1) = 0,61.A solution of 3β-ethynyl-3α-hydroxy-21-hydroxypropylsulfinyl-5β-pregnan-20-one (65 mg, 0.145 mmol), 57% -86% mCPBA (42 mg) and a spatula of sodium bicarbonate in 5 ml of CH2Cl2 was stirred from 0 ° C until room temperature overnight. The mixture was subjected to partition between CH 2 Cl 2 and aqueous sodium bicarbonate. The layer Organic was washed with saturated aqueous NaCl, dried with Na 2 SO 4 and concentrated in vacuo to dryness giving as Outcome 3β-ethynyl-3α-hydroxy-21-hydroxypropylsulfonyl-5β-pregnan-20-one (66 mg) as a white solid; TLC R f (CH 2 Cl 2: acetone 1: 1) = 0.61.
Se preparó de forma similar 3\alpha-hidroxi-21-(3'-hidroxipropilsulfonil)-2\beta-propoxi-5\alpha-pregnan-20-ona; TLC R_{f} (hexano:acetona 2:1) = 0,26.It was prepared similarly 3α-hydroxy-21- (3'-hydroxypropylsulfonyl) -2β-propoxy-5α-pregnan-20-one; TLC R f (hexane: acetone 2: 1) = 0.26.
Ejemplo de Referencia 35Reference Example 35
Se añadieron 3-hidroxipiridina (215 mg, 2,27 milimoles) y K_{2}CO_{3} (313 mg, 2,27 milimoles) a una solución de 3\alpha-hidroxi-21-bromo-5\beta-pregnan-20-ona (300 mg, 0,76 milimoles) en DMF (5 ml) y la mezcla obtenida se agitó a 25ºC durante 0,5 horas. La mezcla se reacción se vertió a continuación en un embudo separador que contenía agua (30 ml) y la mezcla se extrajo con EtOAc (3x35 ml). Los extractos combinados se lavaron con agua (2x 25 ml) y a continuación se secaron sobre Na_{2}SO_{4}. La retirada del disolvente a vacío daba como resultado el producto en bruto que se purificó mediante cromatografía de desarrollo rápido sobre gel de sílice para dar la 3\alpha-hidroxi-21-(pirid-3-il)oxi-5\beta-pregnan-20-ona pura (50 mg); pf 63-66ºC; TLC R_{f} (MeOH:CH_{2}Cl_{2} 5:95) = 0,15.3-hydroxypyridine was added (215 mg, 2.27 mmol) and K 2 CO 3 (313 mg, 2.27 mmol) to a solution of 3α-hydroxy-21-bromo-5β-pregnan-20-one (300 mg, 0.76 mmol) in DMF (5 ml) and the mixture obtained is stirred at 25 ° C for 0.5 hours. The reaction mixture was poured into then in a separatory funnel containing water (30 ml) and the mixture was extracted with EtOAc (3x35 ml). The combined extracts are washed with water (2x 25 ml) and then dried over Na_ {2} SO_ {4}. Solvent removal under vacuum gave as result the raw product that was purified by flash chromatography on silica gel to give the 3α-hydroxy-21- (pyrid-3-yl) oxy-5β-pregnan-20-one pure (50 mg); mp 63-66 ° C; TLC R f (MeOH: CH 2 Cl 2 5:95) = 0.15.
Se añadió etanol (2 ml) a una mezcla de
2\beta-isopropoxi-3\alpha-hidroxi-5\alpha-androstan-17-ona
(700 mg, 2,0 milimoles) y hidrazida de
p-toluenosulfona (450 mg, 2,4 milimoles) y la mezcla
obtenida se calentó hasta reflujo durante 12 horas. A continuación,
la mezcla de reacción se disolvió en CH_{2}Cl_{2} (150 ml) y se
lavó con agua (4x45 ml). Se secó a continuación sobre
Na_{2}SO_{4} y la retirada del disolvente a vacío daba como
resultado la tosilhidrazona de
2\beta-isopropoxi-3\alpha-hidroxi-5\alpha-androstan-17-ona
en bruto (1,113 g), que se usó sin purificación adicional para la
siguiente
etapa.Ethanol (2 ml) was added to a mixture of 2β-isopropoxy-3α-hydroxy-5α-androstan-17-one (700 mg, 2.0 mmol) and p-toluenesulfone hydrazide (450 mg , 2.4 millimoles) and the obtained mixture was heated to reflux for 12 hours. Then, the reaction mixture was dissolved in CH2Cl2 (150 ml) and washed with water (4x45 ml). It was then dried over Na2SO4 and removal of the solvent in vacuo resulted in crude 2β-isopropoxy-3α-hydroxy-5α-androstan-17-one tosylhydrazone ( 1,113 g), which was used without further purification for the following
stage.
Se añadieron DMF y sulfolano (1:1, 3 ml) a una mezcla de tosilhidrazona de 2\beta-isopropoxi-3\alpha-hidroxi-5\alpha-androstan-17-ona (300 mg), NaBH_{3}CN (144 mg) y ácido p-toluenosulfónico (30 mg) y la mezcla obtenida se calentó hasta 110ºC durante 3 horas. A continuación, se añadió una cantidad adicional de NaBH_{3}CN (144 mg) y ácido p-toluenosulfónico (30 mg) y se calentó durante otra hora. Se añadió a continuación agua y la mezcla se extrajo con EtOAc (2x45 ml). Los extractos combinados se secaron sobre Na_{2}SO_{4} y el producto en bruto obtenido mediante la retirada del disolvente se purificó mediante cromatografía de desarrollo rápido sobre gel de sílice para dar el 2\beta-isopropoxi-3\alpha-hidroxi-5\alpha-androstano puro (37 mg); TLC R_{f} (EtOAc:hexano 1:9) = 0,17.DMF and sulfolane (1: 1, 3 ml) were added to a tosylhydrazone mixture of 2β-isopropoxy-3α-hydroxy-5α-androstan-17-one (300 mg), NaBH 3 CN (144 mg) and acid p-toluenesulfonic (30 mg) and the mixture obtained is heated to 110 ° C for 3 hours. Next, a additional amount of NaBH 3 CN (144 mg) and acid p-toluenesulfonic acid (30 mg) and heated during another hour. Water was then added and the mixture was extracted with EtOAc (2x45 ml). The combined extracts were dried over Na 2 SO 4 and the crude product obtained by solvent removal was purified by chromatography of rapid development on silica gel to give the 2β-isopropoxy-3α-hydroxy-5α-androstane pure (37 mg); TLC R f (EtOAc: hexane 1: 9) = 0.17.
\newpage\ newpage
Ejemplo de Referencia 37Reference Example 37
Se añadió una solución de hidruro de litio y tri(terc-butoxi)aluminio a una solución de 5\beta-19-norandrostan-3,17-diona (0,76 g, 2,77 milimoles) en THF (30 ml) a -78ºC. La mezcla de reacción se vertió a continuación en un embudo separador que contenía solución de NH_{4}Cl (50 ml) y el producto se extrajo con EtOAc (3x50 ml). Los extractos combinados se secaron sobre Na_{2}SO_{4} y la retirada del disolvente daba como resultado un producto en bruto que se purificó mediante cromatografía de desarrollo rápido sobre gel de sílice para dar la 3\alpha-hidroxi-5\beta-19-norandrostan-17-ona pura (605 mg); pf 199-161ºC; TLC R_{f} (hexano:acetona 7:3) = 0,30.A solution of lithium hydride was added and tri (tert-butoxy) aluminum at one solution of 5β-19-norandrostan-3.17-dione (0.76 g, 2.77 mmol) in THF (30 ml) at -78 ° C. The mixture of reaction was then poured into a separatory funnel that contained NH4Cl solution (50 ml) and the product was extracted with EtOAc (3x50 ml). The combined extracts were dried over Na 2 SO 4 and solvent removal resulted in a crude product that was purified by chromatography of rapid development on silica gel to give the 3α-hydroxy-5β-19-norandrostan-17-one pure (605 mg); mp 199-161 ° C; TLC R f (hexane: acetone 7: 3) = 0.30.
Se añadió etanol (2 ml) a una mezcla de 3\alpha-hidroxi-5\beta-19-norandrostan-17-ona (0,59 g, 2,13 milimoles) y hidrazida de p-toluenosulfonilo (480 mg, 2,6 milimoles) y la mezcla obtenida se calentó hasta reflujo durante 5 horas. A continuación, la mezcla de reacción se disolvió en CH_{2}Cl_{2} (100 ml) y se lavó con agua (2x30 ml). Se secó a continuación sobre Na_{2}SO_{4} y la retirada del disolvente a vacío daba como resultado el producto en bruto (1,0 g). Este producto en bruto se mezcló con NaBH_{3}CN (555 mg) y ácido p-toluenosulfónico (68 mg) y una mezcla de DMF y sulfolano (1:1, 10 ml) y la mezcla obtenida se calentó hasta 130ºC durante 2 horas. A continuación, se añadió una cantidad adicional de NaBH_{3}CN (200 mg) y ácido p-toluenosulfónico (30 mg) y se calentó durante otra hora. Se añadió a continuación agua (80 ml) y la mezcla se extrajo con EtOAc (3x50 ml). Los extractos combinados se secaron sobre Na_{2}SO_{4} y el producto en bruto obtenido mediante la retirada del disolvente se purificó mediante cromatografía de desarrollo rápido sobre gel de sílice para dar el 3\alpha-hidroxi-5\beta-19-norandrostano puro (217 mg); pf 129-132ºC; TLC R_{f} (EtOAc:hexano 1:9) = 0,30.Ethanol (2 ml) was added to a mixture of 3α-hydroxy-5β-19-norandrostan-17-one (0.59 g, 2.13 mmol) and hydrazide of p-toluenesulfonyl (480 mg, 2.6 mmol) and the obtained mixture was heated to reflux for 5 hours. TO then, the reaction mixture was dissolved in CH2Cl2 (100 ml) and washed with water (2x30 ml). It was then dried over Na2SO4 and solvent removal in vacuo gave as result the raw product (1.0 g). This raw product is mixed with NaBH 3 CN (555 mg) and acid p-toluenesulfonic (68 mg) and a mixture of DMF and sulfolane (1: 1, 10 ml) and the obtained mixture was heated to 130 ° C for 2 hours Then an additional amount was added NaBH 3 CN (200 mg) and p-toluenesulfonic acid (30 mg) and heated for another hour. Was added below water (80 ml) and the mixture was extracted with EtOAc (3x50 ml). The Combined extracts were dried over Na2SO4 and the product Crude obtained by solvent removal was purified by flash chromatography on silica gel to give the 3α-hydroxy-5β-19-norandrostane pure (217 mg); mp 129-132 ° C; TLC R f (EtOAc: hexane 1: 9) = 0.30.
Ejemplo de Referencia 38Reference Example 38
Se añadieron NaOAc (100 mg, 1,2 milimoles) y PCC (520 mg, 2,4 milimoles) a una solución de 3\alpha-hidroxi-5\beta-19-norandrostano (210 mg, 0,8 milimoles) en CH_{2}Cl_{2} (25 ml) y la mezcla obtenida se agitó a 25ºC durante 1 hora. A continuación, la mezcla de reacción se filtró a través de un bloque de Florisil (15 g) en un embudo Buchner eluido con disolvente mixto de éter y CH_{2}Cl_{2} (1:1, 70 ml). El disolvente se retiró a continuación a vacío y el producto en bruto así obtenido se purificó mediante cromatografía de desarrollo rápido para dar la 5\beta-19-norandrostan-3-ona pura (190 mg); TLC R_{f} (EtOAc:hexano 5:95) = 0,20.NaOAc (100 mg, 1.2 mmol) and PCC were added (520 mg, 2.4 millimoles) to a solution of 3α-hydroxy-5β-19-norandrostane (210 mg, 0.8 mmol) in CH 2 Cl 2 (25 ml) and the mixture obtained was stirred at 25 ° C for 1 hour. Then the mixture reaction was filtered through a block of Florisil (15 g) in a Buchner funnel eluted with mixed ether solvent and CH 2 Cl 2 (1: 1, 70 ml). The solvent was removed at then under vacuum and the crude product thus obtained is purified by flash chromatography to give the 5β-19-norandrostan-3-one pure (190 mg); TLC R f (EtOAc: hexane 5:95) = 0.20.
Se añadió n-BuLi (2,5M, 1,8 ml,
4,4 milimoles) a -78ºC a una solución de
1,2-dibromoetileno (410 mg, 2,2 mili-
moles) y
la reacción se agitó a esta temperatura durante 45 minutos. A
continuación, se añadió gota a gota una solución de
5\beta-19-norandrostan-3-ona
(190 mg, 0,63 milimoles) en THF (10 ml) al reactivo de litio
generado. A continuación, la mezcla de reacción se vertió en un
embudo separador que contenía solución de NH_{4}Cl (50 ml) y el
producto se extrajo con EtOAc (3x40 ml). Los extractos combinados se
secaron sobre Na_{2}SO_{4} y el producto en bruto obtenido
mediante la retirada del disolvente se purificó mediante
cromatografía de desarrollo rápido sobre gel de sílice para dar el
3\alpha-hidroxi-3\beta-etinil-5\beta-19-norandrostano
puro (120 mg); p.f. 152-154ºC; TLC R_{f}
(EtOAc:hexano 1:9) = 0,19.N-BuLi (2.5M, 1.8 ml, 4.4 mmol) was added at -78 ° C to a solution of 1,2-dibromoethylene (410 mg, 2.2 milli
moles) and the reaction was stirred at this temperature for 45 minutes. Then, a solution of 5β-19-norandrostan-3-one (190 mg, 0.63 mmol) in THF (10 ml) was added dropwise to the generated lithium reagent. Then, the reaction mixture was poured into a separatory funnel containing NH4Cl solution (50 ml) and the product was extracted with EtOAc (3x40 ml). The combined extracts were dried over Na2SO4 and the crude product obtained by solvent removal was purified by flash chromatography on silica gel to give 3α-hydroxy-3β-ethynyl -5? -19-norandrostane pure (120 mg); mp 152-154 ° C; TLC R f (EtOAc: hexane 1: 9) = 0.19.
Ejemplo de Referencia 39Reference Example 39
Se añadió trietilamina (1,5 ml) a una mezcla de 3\alpha-hidroxi-3\beta-etinil-5\beta-19-norandrostano (120 mg, 0,42 milimoles), 4-yodoacetofenona (115 mg, 0,46 milimoles), cloruro de bis(trifenilfosfina)paladio(II) (cantidad catalítica) y yoduro de cobre(I) (cantidad catalítica) y la mezcla obtenida se agitó bajo argón durante 45 minutos con el matraz envuelto con papel de aluminio. A continuación, se añadió CH_{2}Cl_{2} (5 ml) y la reacción se agitó durante 3 horas. A continuación, el disolvente se retiró a vacío y el residuo se purificó mediante cromatografía de desarrollo rápido sobre gel de sílice para dar el 3\alpha-hidroxi-3\beta-(4'-acetilfenil)etinil-5\beta-19-norandrostano (37 mg); TLC R_{f} (EtOAc:hexano 15:85) = 0,2.Triethylamine (1.5 ml) was added to a mixture of 3α-hydroxy-3β-ethynyl-5β-19-norandrostane (120 mg, 0.42 mmol), 4-iodoacetophenone (115 mg, 0.46 mmol), chloride bis (triphenylphosphine) palladium (II) (quantity catalytic) and copper iodide (I) (catalytic amount) and the obtained mixture was stirred under argon for 45 minutes with the flask wrapped with foil. Then it was added CH 2 Cl 2 (5 ml) and the reaction was stirred for 3 hours. TO then the solvent was removed in vacuo and the residue was purified by flash chromatography on gel silica to give the 3α-hydroxy-3β- (4'-acetylphenyl) ethynyl-5β-19-norandrostane (37 mg); TLC R f (EtOAc: hexane 15:85) = 0.2.
Ejemplo de Referencia 40Reference Example 40
Una solución de
3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano
(250 mg, 0,82 milimoles) en piridina seca (2 ml) se trató con
cloruro de isobutirilo (0,12 ml, 1,15 milimoles) y
N,N-dimetilaminopiridina (5 mg) a 5ºC. Después de
agitar la mezcla a 5-10ºC durante 1 hora, la mezcla
se extinguió con solución de HCl (0,5 N, 25 ml). La mezcla se
extrajo con EtOAc. La capa orgánica se lavó con HCl diluido,
salmuera y agua. Después de secar sobre MgSO_{4} anhidro, la
solución se filtró y se evaporó para dar el producto en bruto. Este
producto en bruto se disolvió a continuación en una pequeña
cantidad de CH_{2}Cl_{2} y se vertió en una columna de gel de
sílice. La elución con mezcla de hexano:acetona (9:1) daba
3\alpha-isobutiriloxi-17\beta-metoxi-5\beta-androstano
(266 mg); pf 82-87ºC; TLC R_{f} (hexano:acetona
9:1)
= 0,6.A solution of 3α-hydroxy-17β-methoxy-5β-androstane (250 mg, 0.82 mmol) in dry pyridine (2 ml) was treated with isobutyryl chloride (0.12 ml, 1, 15 mmol) and N, N-dimethylaminopyridine (5 mg) at 5 ° C. After stirring the mixture at 5-10 ° C for 1 hour, the mixture was quenched with HCl solution (0.5 N, 25 ml). The mixture was extracted with EtOAc. The organic layer was washed with dilute HCl, brine and water. After drying over anhydrous MgSO4, the solution was filtered and evaporated to give the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured onto a silica gel column. Elution with hexane: acetone mixture (9: 1) gave 3α-isobutyryloxy-17β-methoxy-5β-androstane (266 mg); mp 82-87 ° C; TLC R f (hexane: acetone 9: 1)
= 0.6.
Ejemplo de Referencia 41Reference Example 41
Una solución de 21-bromo-3\alpha-hidroxi-5\beta-pregnan-20-ona (500 mg, 1,26 milimoles), 4-hidroxipridina (144 mg, 1,51 milimoles) y trietilamina (200 \mul) en 10 ml de THF se calentó bajo reflujo durante 4 horas. La mezcla se enfrió hasta temperatura ambiente y se sometió a reparto entre EtOAc y agua. La capa orgánica se lavó con NaCl acuoso saturado, se secó con MgSO_{4} y se concentró a vacío. El residuo en bruto se sometió a cromatografía en columna de desarrollo rápido. La elución con acetona al 50% en CH_{2}Cl_{2} daba 3\alpha-hidroxi-21-(pirid-4-iloxi)-5\beta-pregnan-20-ona (40 mg) como un sólido aceitoso; TLC R_{f} (acetona:CH_{2}Cl_{2} 1:1) = 0,28.A solution of 21-bromo-3α-hydroxy-5β-pregnan-20-one (500 mg, 1.26 mmol), 4-hydroxyridine (144 mg, 1.51 mmol) and triethylamine (200 µl) in 10 ml of THF are heated under reflux for 4 hours. The mixture was cooled until room temperature and was partitioned between EtOAc and water. The Organic layer was washed with saturated aqueous NaCl, dried with MgSO4 and concentrated in vacuo. The crude residue was subjected to column chromatography of rapid development. Elution with 50% acetone in CH 2 Cl 2 gave 3α-hydroxy-21- (pyrid-4-yloxy) -5β-pregnan-20-one (40 mg) as an oily solid; TLC R f (acetone: CH 2 Cl 2 1: 1) = 0.28.
Ejemplo de Referencia 42Reference Example 42
Una solución de 21-bromo-3\alpha-hidroxi-3\beta-metil-5\alpha-pregnan-20-ona (250 mg, 0,61 milimoles), 4-nitrofenol (127 mg, 0,912 milimoles), trietilamina (12700 \mul, 0,912 milimoles) y una pequeña cantidad de yoduro sódico en acetonitrilo:DMF 2:1 se agitó con calentamiento hasta \sim60ºC durante 6 horas. La mezcla se sometió a reparto entre EtOAc y agua:bicarbonato sódico saturado 1:1. La capa orgánica se lavó con HCl 2N, agua y NaCl acuoso saturado, se secó con Na_{2}SO_{4} y se concentró a vacío. El residuo en bruto se sometió a cromatografía en columna de desarrollo rápido. La elución con acetona al 20% en hexano daba 3\alpha-hidroxi-3\beta-metil-21-(4'-nitrofenoxi)-5\alpha-pregnan-20-ona (147 mg) como un sólido; pf 169-172ºC; TLC R_{f} (hexano:acetona 4:1) = 0,35.A solution of 21-bromo-3α-hydroxy-3β-methyl-5α-pregnan-20-one (250 mg, 0.61 mmol), 4-nitrophenol (127 mg, 0.912 mmol), triethylamine (12700 µL, 0.912 mmol) and a small amount of sodium iodide in acetonitrile: DMF 2: 1 se stirred with heating to ~ 60 ° C for 6 hours. Mix was partitioned between EtOAc and water: saturated sodium bicarbonate 1: 1. The organic layer was washed with 2N HCl, water and aqueous NaCl saturated, dried with Na2SO4 and concentrated in vacuo. He crude residue was subjected to column chromatography of rapid development Elution with 20% acetone in hexane gave 3α-hydroxy-3β-methyl-21- (4'-nitrophenoxy) -5α-pregnan-20-one (147 mg) as a solid; mp 169-172 ° C; TLC R f (hexane: acetone 4: 1) = 0.35.
Se preparó de forma similar
3\alpha-hidroxi-3\beta-metil-21-(quinolin-6-iloxi)-5\alpha-pregnan-20-ona;
TLC R_{f} (hexano:aceto-
na 3:1) = 0,22.3α-hydroxy-3β-methyl-21- (quinolin-6-yloxy) -5α-pregnan-20-one was prepared similarly; TLC R f (hexane: aceto-
na 3: 1) = 0.22.
Ejemplo de Referencia 43Reference Example 43
Una solución de 3\alpha-hidroxi-3\beta-metil-21-(4'-nitrofenoxi)-5\alpha-pregnan-20-ona (100 mg, 0,213 milimoles), formaldehído (solución al 37% en agua, 800 ml) y Pd al 5%/C (30 g, catalítico) en etanol se puso bajo una atmósfera de H_{2} a 3,7 kg/cm^{2} (53 psi) en un agitador de Parr durante la noche. El catalizador se separó por filtración lavando con EtOAc y el filtrado se lavó en un embudo separador con agua y NaCl acuoso saturado. La capa orgánica se secó a continuación con Na_{2}SO_{4} y se concentró a vacío. El residuo en bruto se sometió a cromatografía en columna de desarrollo rápido. La elución con acetona al 20% en hexano daba 21-(4'-dimetilaminofenoxi)-3\alpha-hidroxi-3\beta-metil-5\alpha-pregnan-20-ona (64 mg) como una espuma; TLC R_{f} (hexano:acetona 2:1) = 0,55.A solution of 3α-hydroxy-3β-methyl-21- (4'-nitrophenoxy) -5α-pregnan-20-one (100 mg, 0.213 mmol), formaldehyde (37% solution in water, 800 ml) and 5% Pd / C (30 g, catalytic) in ethanol was placed under a atmosphere of H2 at 3.7 kg / cm2 (53 psi) on a stirrer Parr during the night. The catalyst was filtered off. washing with EtOAc and the filtrate was washed in a separatory funnel with water and saturated aqueous NaCl. The organic layer was dried at then with Na2SO4 and concentrated in vacuo. The residue raw underwent developmental column chromatography Quick. Elution with 20% acetone in hexane gave 21- (4'-dimethylaminophenoxy) -3α-hydroxy-3β-methyl-5α-pregnan-20-one (64 mg) as a foam; TLC R f (hexane: acetone 2: 1) = 0.55.
Se preparó de forma similar 21-(4'-dimetilaminofeniltio)-3\alpha-hidroxi-3\beta-metoximetil-5\alpha-pregnan-20-ona; TLC R_{f} (hexano:acetona 3:1) = 0,35.It was prepared similarly 21- (4'-dimethylaminophenylthio) -3α-hydroxy-3β-methoxymethyl-5α-pregnan-20-one; TLC R f (hexane: acetone 3: 1) = 0.35.
Ejemplo de Referencia 44Reference Example 44
Una solución de 3\alpha-hidroxi-3\beta-metoximetil-21-(4'-nitrofeniltio)-5\alpha-pregnan-20-ona (120 mg, 0,23 milimoles), mCPBA al 57%-86% (111 mg) y NaHCO_{3} (80 m g, 4 eq.) en CH_{2}Cl_{2} se agitó a de 0ºC a temperatura ambiente durante 2 horas. La reacción se sometió a reparto entre CH_{2}Cl_{2} y NaHCO_{3} acuoso. La capa orgánica se lavó en NaCl acuoso saturado y a continuación se secó con Na_{2}SO_{4} y se concentró a vacío. El residuo en bruto se sometió a cromatografía en columna de desarrollo rápido. La elución con EtOAc al 40%-50% daba 3\alpha-hidroxi-3\beta-metoximetil-21-(4'-nitrofenilsulfonil)-5\alpha-pregnan-20-ona (65 mg) como un sólido. TLC R_{f} (hexano:EtOAc 1:1) = 0,38, seguido por 3\alpha-hidroxi-3\beta-metoximetil-21-(R)-(4'-nitrofenilsulfinil)-5\alpha-pregnan-20-ona y 3\alpha-hidroxi-3\beta-metoximetil-21-(S)-(4'-nitrofenilsulfinil)-5\alpha-pregnan-20-ona en orden no identificado.A solution of 3α-hydroxy-3β-methoxymethyl-21- (4'-nitrophenylthio) -5α-pregnan-20-one (120 mg, 0.23 mmol), 57% -86% mCPBA (111 mg) and NaHCO 3 (80 μg, 4 eq.) In CH 2 Cl 2 was stirred at 0 ° C at temperature atmosphere for 2 hours. The reaction was partitioned between CH 2 Cl 2 and aqueous NaHCO 3. The organic layer was washed in Saturated aqueous NaCl and then dried with Na2SO4 and concentrated in vacuo. The crude residue was subjected to column chromatography of rapid development. Elution with EtOAc at 40% -50% gave 3α-hydroxy-3β-methoxymethyl-21- (4'-nitrophenylsulfonyl) -5α-pregnan-20-one (65 mg) as a solid. TLC R f (hexane: EtOAc 1: 1) = 0.38, followed by 3α-hydroxy-3β-methoxymethyl-21- (R) - (4'-nitrophenylsulfinyl) -5α-pregnan-20-one Y 3α-hydroxy-3β-methoxymethyl-21- (S) - (4'-nitrophenylsulfinyl) -5α-pregnan-20-one in unidentified order.
Se preparó de forma similar 21-(4'-fluorofenil)sulfonil-3\alpha-hidroxi-3\beta-metoximetil-5\alpha-pregnan-20-ona.It was prepared similarly 21- (4'-fluorophenyl) sulfonyl-3α-hydroxy-3β-methoxymethyl-5α-pregnan-20-one.
\newpage\ newpage
Ejemplo de Referencia 45Reference Example Four. Five
Una solución de
21-(4'-fluorofenil)sulfonil-3\alpha-hidroxi-3\beta-metoximetil-5\alpha-pregnan-20-ona
(100 mg, 0,192 milimoles) y pirrolidina (21 \mul, 0,25 milimoles)
en 5 ml de DMSO se calentó en un baño de aceite a 100ºC durante 5
horas y a continuación se agitó a ta durante la noche. Se añadió a
continuación agua y la mezcla se extrajo con CH_{2}Cl_{2}. La
fase orgánica se secó con Na_{2}SO_{4} y se concentró a vacío.
El residuo se sometió a cromatografía en columna de desarrollo
rápido eluyendo con hexano:EtOAc para dar el compuesto del título
(62 mg) como un sólido amari-
llo.A solution of 21- (4'-fluorophenyl) sulfonyl-3α-hydroxy-3β-methoxymethyl-5α-pregnan-20-one (100 mg, 0.192 mmol) and pyrrolidine (21 µL, 0, 25 mmol) in 5 ml of DMSO was heated in an oil bath at 100 ° C for 5 hours and then stirred at rt overnight. Water was then added and the mixture was extracted with CH2Cl2. The organic phase was dried with Na2SO4 and concentrated in vacuo. The residue was subjected to flash column chromatography eluting with hexane: EtOAc to give the title compound (62 mg) as a yellow solid.
llo.
Ejemplo de Referencia 46Reference Example 46
Una solución de etóxido sódico, preparada a partir de 300 mg de sodio y 10 ml de etanol, se añadió a una solución de 3\alpha-hidroxi-5\beta-pregnan-20-ona (500 mg, 1,57 milimoles) y piridin-4-carboxaldehído (165 \mul, 1,73 milimoles) en 10 ml de etanol a través de una cánula. La mezcla se agitó vigorosamente a ta durante 30 horas. Precipitaba un sólido y se filtró y se lavó con etanol, a continuación se secó bajo vacío dando como resultado el compuesto del título (260 mg).A solution of sodium ethoxide, prepared at from 300 mg of sodium and 10 ml of ethanol, it was added to a solution of 3α-hydroxy-5β-pregnan-20-one (500 mg, 1.57 mmol) and pyridin-4-carboxaldehyde (165 [mu], 1.73 mmol) in 10 ml of ethanol through a cannula. The mixture was vigorously stirred at rt for 30 hours. Precipitated a solid and filtered and washed with ethanol, then dried under vacuum resulting in the title compound (260 mg)
Ejemplo de Referencia 47Reference Example 47
Una solución de 3\alpha-hidroxi-21-(4-piridilmetilen)-5\beta-pregnan-20-ona (100 mg, 0,245 milimoles) en 4 ml de cada uno de etano y THF que contenía 20 mg de Pd al 5%/C se sometió a atmósfera de hidrógeno a través de un globo y se agitó durante 5 horas. El catalizador se separó a continuación por filtración y la solución se concentró a vacío. El residuo se sometió a cromatografía en columna de desarrollo rápido eluyendo con hexano:acetona para dar el compuesto del título (38 mg) como un sólido; TLC R_{f} (hexano:acetona 2:1) = 0,28.A solution of 3α-hydroxy-21- (4-pyridylmethylene) -5β-pregnan-20-one (100 mg, 0.245 mmol) in 4 ml each of ethane and THF which containing 20 mg of 5% Pd / C was subjected to hydrogen atmosphere at through a balloon and stirred for 5 hours. The catalyst is then filtered off and the solution was concentrated to empty. The residue was subjected to column chromatography of rapid development eluting with hexane: acetone to give the compound of the title (38 mg) as a solid; TLC R f (hexane: acetone 2: 1) = 0.28.
Ejemplo de Referencia 48Reference Example 48
Una mezcla de 3\alpha-hidroxi-3\beta-trifluorometil-5\beta-pregnan-20-ona (1,0 g, 268 milimoles), L-tartrato de dimetilo (1,0 g, 5,61 milimoles), monohidrato de ácido p-toluenosulfónico (13 mg, 0,068 milimoles) y ortoformiato de trimetilo (0,38 ml) en 15 ml de tolueno se calentó a reflujo con retirada azeotrópica de agua. Después de 1 hora, la reacción se dejó enfriar hasta ta y se añadió NaHCO_{3} sólido (130 mg). La mezcla resultante se sometió a reparto entre una solución acuosa saturada de NaHCO_{3} y acetato de etilo. La capa acuosa se separó y se lavó dos veces con acetato de etilo (2 x 20 ml). Las capas de acetato de etilo combinadas se lavaron con una solución saturada de NaCl, se secaron (Na_{2}SO_{4}) y se concentraron a vacío. El residuo se cromatografió (acetona al 17,5%/hexano) dando una espuma blanca que se trituró con hexano proporcionando el éster dimetílico como un sólido blanco. Una solución del diéster en metanol (2 ml) y agua (1 ml) se trató con KOH sólido (78 mg). Después de agitar durante la noche, la reacción se concentró hasta sequedad dando el compuesto del título como un sólido amarillo claro.A mix of 3α-hydroxy-3β-trifluoromethyl-5β-pregnan-20-one (1.0 g, 268 mmol), dimethyl L-tartrate (1.0 g, 5.61 mmol), acid monohydrate p-toluenesulfonic acid (13 mg, 0.068 mmol) and Trimethyl orthoformate (0.38 ml) in 15 ml of toluene was heated at reflux with azeotropic water withdrawal. After 1 hour, the reaction was allowed to cool to rt and solid NaHCO3 was added (130 mg) The resulting mixture was partitioned between a saturated aqueous solution of NaHCO3 and ethyl acetate. The layer aqueous was separated and washed twice with ethyl acetate (2 x 20 ml) The combined ethyl acetate layers were washed with a saturated NaCl solution, dried (Na2SO4) and dried concentrated in vacuo. The residue was chromatographed (acetone at 17.5% / hexane) giving a white foam that was triturated with hexane providing the dimethyl ester as a white solid. A solution of the diester in methanol (2 ml) and water (1 ml) was treated with Solid KOH (78 mg). After stirring overnight, the reaction concentrated to dryness giving the title compound as a light yellow solid.
Los datos experimentales in vitro e in vivo muestran que los metabolitos presentes en la naturaleza de progesterona/desoxicorticosterona y sus derivados interactúan con alta afinidad en un sitio de reconocimiento nuevo y específico en el GRC para facilitar la conductancia de iones cloruro a través de membranas neuronales sensibles a GABA (Gee, K.W. y otros, European Journal of Pharmacology, 136:419-423 (1987); Harrison, N.L. y otros, J. Pharmacol. Exp. Ther. 241:346-353 (1987)). In vitro and in vivo experimental data show that metabolites present in the nature of progesterone / deoxycorticosterone and its derivatives interact with high affinity at a new and specific recognition site in the GRC to facilitate the conductance of chloride ions through neuronal membranes sensitive to GABA (Gee, KW et al., European Journal of Pharmacology, 136 : 419-423 (1987); Harrison, NL et al., J. Pharmacol. Exp. Ther. 241 : 346-353 (1987)).
Para los expertos en la especialidad, es sabido que la modulación de la unión a [^{35}S]biciclofosforotioato de t-butilo ([^{35}S]TBPS) es una medida de la potencia y la eficacia de fármacos que actúan sobre el GRC, fármacos que pueden ser de valor terapéutico potencial en el tratamiento del estrés, la ansiedad y trastornos epilépticos (Squires, R.F. y otros, Mol. Pharmacol., 23:326 (1983); Lawrence, L.J. y otros, Biochem. Biophys. Res. Commn., 123:1130-1137 (1984); Wood y otros, Pharmacol, Exp. Ther., 231:572-576 (1984)). Se realizaron previamente varios experimentos para determinar la naturaleza de la modulación de [^{35}S]TBPS que está afectada por esteroides neuroactivos. Se encontró que estos compuestos interactúan con un nuevo sitio en el GRC que no se solapa con los sitios de barbiturato, benzodiazepina o cualesquiera otros previamente conocidos. Por otra parte, estos compuestos tienen alta potencia y eficacia en el GRC, con requisitos estructurales estrictos para tal actividad.For those skilled in the art, it is known that modulation of the [35 S] binding of t-butyl bicyclophosphorothioate ([35 S] TBPS) is a measure of the potency and efficacy of drugs that they act on the GRC, drugs that can be of potential therapeutic value in the treatment of stress, anxiety and epileptic disorders (Squires, RF et al., Mol. Pharmacol., 23 : 326 (1983); Lawrence, LJ et al., Biochem Biophys. Res. Commn., 123 : 1130-1137 (1984); Wood et al., Pharmacol, Exp. Ther., 231 : 572-576 (1984)). Several experiments were previously performed to determine the nature of the modulation of [35 S] TBPS that is affected by neuroactive steroids. These compounds were found to interact with a new site in the GRC that does not overlap with the sites of barbiturate, benzodiazepine or any other previously known. On the other hand, these compounds have high potency and efficiency in the GRC, with strict structural requirements for such activity.
Los procedimientos para realizar este ensayo se describen a fondo en: (1) Gee, K.W. y otros, European Journal of Pharmacology, 136:419-423 (1987) y (2) Gee y otros, Molecular Pharmacology 30:218 (1986). Estos procedimientos se realizaron como sigue:The procedures for performing this assay are described in depth in: (1) Gee, KW and others, European Journal of Pharmacology, 136 : 419-423 (1987) and (2) Gee and others, Molecular Pharmacology 30 : 218 (1986) . These procedures were performed as follows:
Cerebros de ratas Sprague-Dawley macho se extirparon inmediatamente después del sacrificio y los córtices cerebrales se disecaron sobre hielo. Se preparó un homogenado de P_{2} según se describe previamente (Gee y otros, Molecular Pharmacology 30:218 (1986). Brevemente, los córtices se homogeneizaron suavemente en sacarosa 0,32 M seguido por centrifugación a 1000 x g durante 10 minutos. El sobrenadante se recogió y se centrifugó a 9000 x g durante 20 minutos. El nódulo P_{2} resultante se suspendió como una suspensión al 10% (peso en húmedo/volumen original) en tampón de fosfato Na/K 50 mM (pH 7,4), NaCl 200 mM, para formar el homogenado.Brains of male Sprague-Dawley rats were removed immediately after sacrifice and the cerebral cortices were dissected on ice. A P2 homogenate was prepared as previously described (Gee et al., Molecular Pharmacology 30 : 218 (1986). Briefly, the cortices were gently homogenized in 0.32 M sucrose followed by centrifugation at 1000 xg for 10 minutes. The supernatant was collected and centrifuged at 9000 xg for 20 minutes.The resulting P2 nodule was suspended as a 10% suspension (wet weight / original volume) in 50 mM Na / K phosphate buffer (pH 7, 4), 200 mM NaCl, to form the homogenate.
Partes alícuotas de 100 microlitros (\mul) del homogenado P_{2} (0,5 miligramos (mg) de proteína) se incubaron con [^{35}S]TBPS 2 nanomolar (nM) (70-110 curios/milimol; New England Nuclear, Boston, MA) en presencia o ausencia de los esteroides presentes en la naturaleza o sus derivados sintéticos que han de probarse. Los compuestos probados se disolvieron en dimetilsulfóxido (Baker Chem. Co., Phillipsburg, NJ) y se añadieron a la mezcla de incubación en partes alícuotas de 5 \mul. La mezcla de incubación se llevó hasta un volumen final de 1 ml con tampón. La unión no específica se definió como la unión en presencia de TBPS 2 mM. El efecto y la especificidad de GABA (Sigma Chem. Co., St. Louis, MO) se evaluó realizando todos los ensayos en presencia de GABA más (+) bicuculina (Sigma Chem. Co.). Las incubaciones mantenidas a 25ºC durante 90 minutos (condiciones de estado estacionario) se terminaron mediante filtración rápida a través de filtros de fibra de vidrio (Nº 32, Schleicher y Schuell, Kreene, NH). La radiactividad unida a los filtros se cuantificó mediante espectrofotometría de centelleo de líquidos. Los datos cinéticos y las curvas de respuesta a la dosis de compuesto/[^{35}S]TBPS se analizaron mediante regresión no lineal usando un procedimiento iterativo computarizado para obtener constantes de velocidad y los valores de IC_{50}(concentración de compuesto a la que se produce la inhibición semimáxima de la unión basal a [^{35}S]TBPS).100 microliters (\ mul) aliquots of the P2 homogenate (0.5 milligrams (mg) protein) were incubated with [35 S] 2 nanomolar TBPS (nM) (70-110 curios / millimol; New England Nuclear, Boston, MA) in the presence or absence of steroids present in nature or their synthetic derivatives to be tested. The compounds tested they were dissolved in dimethylsulfoxide (Baker Chem. Co., Phillipsburg, NJ) and were added to the incubation mixture in aliquots of 5 \ mul. The incubation mixture was brought to a final volume. 1 ml with buffer. Non-specific binding was defined as the union in the presence of 2 mM TBPS. The effect and specificity of GABA (Sigma Chem. Co., St. Louis, MO) was evaluated by performing all trials in the presence of GABA plus (+) bicuculin (Sigma Chem. Co.). Incubations maintained at 25 ° C for 90 minutes (conditions steady state) were terminated by rapid filtration at through fiberglass filters (No. 32, Schleicher and Schuell, Kreene, NH). The radioactivity bound to the filters was quantified by liquid scintillation spectrophotometry. The data Kinetic and dose response curves of compound / [35 S] TBPS were analyzed by non-regression linear using a computerized iterative procedure to obtain speed constants and values of IC 50 (concentration of compound at which the semi-maximal inhibition of basal union at [35 S] TBPS).
Se rastrearon diversos compuestos para determinar su potencial como moduladores de la unión a [^{35}S]TBPS in vitro. Estos ensayos se realizaron de acuerdo con los procedimientos analizados previamente. Basándose en estos ensayos, se han establecido los requisitos de estructura-actividad para su interacción específica en el GRC y su orden de rango de potencia y eficacia. Datos experimentales obtenidos en este ensayo para un número de derivados de 3\alpha-hidroxipregnan-20-ona se analizan en (Gee, K.W. y otros, European Journal of Pharmacology, 136:419-423 (1987) y en la Patente de EE.UU. Nº 5.232.917. La Tabla 1 proporciona medidas de IC_{50} e inhibición máxima (I_{MAX}) para numerosos compuestos, incluyendo ejemplos de compuestos descritos y reivindicados aquí. La IC_{50} se define como la concentración de compuestos para inhibir el 50% de la unión a [^{35}S]TBPS de control. Es una indicación de la potencia in vitro del compuesto. La inhibición máxima es una indicación de una eficacia in vitro del compuesto.Various compounds were screened to determine their potential as binding modulators to [35 S] TBPS in vitro . These tests were performed according to the procedures previously analyzed. Based on these trials, the structure-activity requirements for their specific interaction in the GRC and their order of power range and efficacy have been established. Experimental data obtained in this assay for a number of 3α-hydroxypregnan-20-one derivatives are analyzed in (Gee, KW et al., European Journal of Pharmacology, 136 : 419-423 (1987) and in US Pat. US No. 5,232,917, Table 1 provides measures of IC 50 and maximum inhibition (I MAX) for numerous compounds, including examples of compounds described and claimed herein, IC 50 is defined as the concentration of compounds to inhibit 50% of the binding to [35 S] control TBPS.It is an indication of the in vitro potency of the compound.Maximum inhibition is an indication of an in vitro efficacy of the compound.
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Como puede observase a partir de la Tabla 1, la 3\alpha-hidroxi-5\alpha-pregnan-20-ona, la 3\alpha,21-dihidroxi-5\alpha-pregnan-20-ona y los compuestos de la presente invención tienen baja IC_{50}, que es la concentración necesaria para alcanzar el 50% de inhibición máxima de la unión [^{35}S]TBPS, mientras que compuestos tales como esteroides sexuales (R5020, estradiol y progesterona), glucocorticoides (corticosterona) y colesterol, que tienen una IC_{50} alta, son esencialmente inactivos. Así, se anticipa que los esteroides hormonales y el colesterol de por sí no tendrán valor terapéutico para las indicaciones descritas aquí. Para distinguir esta clase única de esteroides de las hormonas sexuales, se denominan ahora "esteroides neuroactivos". Sin embargo, esteroides sexuales tales como la progesterona pueden metabolizarse en el cuerpo hasta esteroides similares a 3\alpha-hidroxi-5\alpha-pregnan-20-ona. Así, la progesterona puede considerase un profármaco de "esteroide neuroactivo". Los datos de TBPS se correlacionan bien con los datos sobre la absorción de iones ^{36}Cl potenciada por diversos esteroides hidroxilados en 3\alpha descritos en Purdy R.H. y otros, J. Med. Chem. 33:1572-1581 (1990). Estos datos también se correlacionan bien con datos electrofisiológicos obtenidos midiendo la actividad de esteroides para potenciar la corriente inducida por GABA en oocitos inyectados con receptores de GABA humanos, según se describe en Hawkinson, J.E. y otros, Mol. Pharmacol. 46:977-985 (1995). Esto indica que el ensayo de TBPS es una medida aproximada de la capacidad de los esteroides para modular alostéricamente la actividad de canales de Cl^{-}.As can be seen from Table 1, 3α-hydroxy-5α-pregnan-20-one, 3α, 21-dihydroxy-5α-pregnan-20-one and the compounds of the The present invention has low IC 50, which is the concentration necessary to reach 50% maximum inhibition of [35 S] TBPS binding, while compounds such as sex steroids (R5020, estradiol and progesterone), glucocorticoids (corticosterone) and cholesterol, which have a high IC 50, are essentially inactive. Thus, it is anticipated that hormonal steroids and cholesterol alone will not have therapeutic value for the indications described here. To distinguish this unique class of steroids from sex hormones, they are now called "neuroactive steroids." However, sex steroids such as progesterone can be metabolized in the body to steroids similar to 3α-hydroxy-5α-pregnan-20-one. Thus, progesterone can be considered a "neuroactive steroid" prodrug. The TBPS data correlate well with the data on the absorption of 36 Cl ions enhanced by various 3α hydroxylated steroids described in Purdy RH et al., J. Med. Chem. 33 : 1572-1581 (1990) . These data also correlate well with electrophysiological data obtained by measuring steroid activity to enhance the current induced by GABA in oocytes injected with human GABA receptors, as described in Hawkinson, JE et al., Mol. Pharmacol 46 : 977-985 (1995). This indicates that the TBPS assay is an approximate measure of the ability of steroids to allosterically modulate Cl - channel activity.
En tanto que la actividad terapéutica deseada debe estar disponible para el paciente con los menos efectos secundarios no deseables, esta invención también implica el descubrimiento de nuevos agonistas con actividad parcial. (Tabla 1, compuestos con I_{MAX} < 100%). Para pacientes que desean la mejora de ansiedad o convulsiones, la hipnosis no se desea. Para los pacientes que desean la mejora del insomnio, los efectos anestésicos no son deseables. Se espera que los compuestos descritos como agonistas con actividad parcial proporcionen el efecto deseado con efectos secundarios no deseados mínimos.While the desired therapeutic activity must be available to the patient with the least effects undesirable side effects, this invention also involves the discovery of new agonists with partial activity. (Table 1, compounds with I_ {MAX} <100%). For patients who want the Improved anxiety or seizures, hypnosis is not desired. For Patients who wish to improve insomnia, the effects Anesthetics are not desirable. Compounds are expected described as agonists with partial activity provide the desired effect with minimal unwanted side effects.
Las correlaciones entre los niveles reducidos de progesterona y los síntomas asociados con PMS, PND y epilepsia catamenial (Backstrom, T. y otros, J. Phychosom. Obstet. Gyanecol. 2:8-20 (1983)); Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2ª edición, Chicago Yearbook, Chicago (1984)) conducen al uso de progesterona en su tratamiento (Mattson y otros, "Medroxyprogesterone therapy of catamenial epilepsy" en Advances in epileptology: XVth Epilepsy International Symposium, Raven Press, Nueva York (1984), pp. 279-282; Dalton, K. Premenstrual Syndrome and Progesterone Therapy, 2ª edición, Chicago Yearbook, Chicago (1984)). Sin embargo, la progesterona no es consecuentemente eficaz en el tratamiento de los síndromes mencionados previamente. Por ejemplo, no existe una relación dosis-respuesta para la progesterona en el tratamiento de PMS (Maddocks y otros (1986). Estos resultados son predecibles cuando se consideran a la luz de los resultados de los presentes estudios in vitro que demuestran que la progesterona tiene muy poca potencia en el GRC, según se observa en la Tabla 1, en comparación con esteroides neuroactivos descritos en esta invención.Correlations between reduced levels of progesterone and the symptoms associated with PMS, PND and catamenial epilepsy (Backstrom, T. et al., J. Phychosom. Obstet. Gyanecol. 2 : 8-20 (1983)); Dalton, K., Premenstrual Syndrome and Progesterone Therapy , 2nd edition, Chicago Yearbook, Chicago (1984)) lead to the use of progesterone in its treatment (Mattson et al., "Medroxyprogesterone therapy of catamenial epilepsy" in Advances in epileptology: XVth Epilepsy International Symposium , Raven Press, New York (1984), pp. 279-282; Dalton, K. Premenstrual Syndrome and Progesterone Therapy , 2nd edition, Chicago Yearbook, Chicago (1984)). However, progesterone is not consistently effective in the treatment of the previously mentioned syndromes. For example, there is no dose-response relationship for progesterone in the treatment of PMS (Maddocks et al. (1986). These results are predictable when considered in light of the results of the present in vitro studies demonstrating that progesterone It has very little power in the GRC, as seen in Table 1, compared to neuroactive steroids described in this invention.
El efecto beneficioso de la progesterona se relaciona probablemente con la conversión variable de progesterona en los metabolitos de progesterona activos que actúan en el receptor de GABA_{A}. El uso de esteroides neuroactivos específicos en el tratamiento de los síndromes mencionados previamente es claramente superior al uso de la progesterona basándose en la alta potencia y eficacia de estos compuestos (véase Gee, K.W. y otros, European Journal of Pharmacology, 136:419-423 (1987) y la Tabla 1, previamente).The beneficial effect of progesterone is probably related to the variable conversion of progesterone into the active progesterone metabolites that act on the GABA A receptor. The use of specific neuroactive steroids in the treatment of the aforementioned syndromes is clearly superior to the use of progesterone based on the high potency and efficacy of these compounds (see Gee, KW et al., European Journal of Pharmacology, 136 : 419-423 (1987) and Table 1, previously).
También se ha demostrado que los esteroides neuroactivos carecen de efectos secundarios hormonales por la falta de afinidad para los receptores de progesterona y otros esteroides hormonales (Tablas 2-5). Los datos presentados se obtuvieron realizando ensayos de acuerdo con los procedimientos descritos previamente para determinar el efecto de metabolitos de progesterona y sus derivados y la progestina R5020 sobre la unión de [^{3}H]R5020 al receptor de progesterona en útero de rata (Gee y otros, Journal of Pharmacology and Experimental Therapeutics 246:803-812 (1988).It has also been shown that neuroactive steroids lack hormonal side effects due to the lack of affinity for progesterone receptors and other hormonal steroids (Tables 2-5). The data presented were obtained by conducting tests in accordance with the procedures previously described to determine the effect of progesterone metabolites and their derivatives and progestin R5020 on the binding of [3 H] R5020 to the progesterone receptor in rat uterus ( Gee et al., Journal of Pharmacology and Experimental Therapeutics 246 : 803-812 (1988).
Se incubó ^{3}H-progesterona (0,15 nM) con el citosol de útero de rata en presencia de los compuestos de prueba. Las uniones específicas se determinaron después de la incubación y se compararon con la incubación de control sin los compuestos. Los datos se expresan como porcentaje de inhibición de la unión. Si los compuestos se unen al receptor de progesterona con alta afinidad, se esperaría una inhibición de 100% de la unión a la concentración probada.3 H-progesterone was incubated (0.15 nM) with the rat uterus cytosol in the presence of test compounds Specific junctions were determined after incubation and compared with incubation of Control without the compounds. Data are expressed as a percentage. of inhibition of the union. If the compounds bind to the receptor of progesterone with high affinity, a 100% inhibition would be expected from binding to proven concentration.
Diversas actividades hormonales de esteroides neuroactivos representativos se estudiaron adicionalmente a través de probar sus actividades estrogénicas, mineralocorticoides y glucocorticoides potenciales. Estas actividades se analizaron controlando la capacidad de los compuestos para inhibir la unión de las hormonas esteroideas a sus receptores de hormonas respectivos. Los resultados se muestran en las Tablas 3-5. Se expresan como porcentaje de inhibición de la unión del ^{3}H-ligando a los diversos receptores de hormonas esteroideas para los compuestos a 10^{-6}M. Los valores de control se representan mediante la unión en ausencia de compuestos de prueba.Various hormonal steroid activities Representative neuroactives were further studied through to test their estrogenic, mineralocorticoid and potential glucocorticoids. These activities were analyzed. controlling the ability of the compounds to inhibit the binding of Steroid hormones to their respective hormone receptors. The results are shown in Tables 3-5. Be express as a percentage of inhibition of the binding of 3 H-ligand to the various receptors of steroid hormones for compounds at 10-6 M. The values of control are represented by binding in the absence of test compounds
En la Tabla 4, las ratas se adrenalectomizaron 3 días antes del sacrificio. Para aislar el receptor de mineralocorticoides, se prepararon fracciones de citosol cerebral según se describe en Gee y otros, Journal of Pharmacology and Experimental Therapeutics 246:803-812 (1988). Los fármacos se incubaron con 3 nM de ^{3}H-aldosterona (el ligando específico para el receptor de mineralocorticoides) en presencia del agonista de tipo II selectivo RU28362 (0,5 \muM) que bloquea la unión de ^{3}H-aldosterona a los receptores de tipo II (de glucocorticoides).In Table 4, the rats were adrenalectomized 3 days before slaughter. To isolate the mineralocorticoid receptor, cerebral cytosol fractions were prepared as described in Gee et al., Journal of Pharmacology and Experimental Therapeutics 246 : 803-812 (1988). The drugs were incubated with 3 nM 3 H-aldosterone (the specific ligand for the mineralocorticoid receptor) in the presence of the selective type II agonist RU28362 (0.5 µM) that blocks the binding of 3 H-aldosterone to type II (glucocorticoid) receptors.
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Para la Tabla 4, se prepararon fracciones de citosol cerebral como para la Tabla 3 y los compuestos se incubaron con 3 nM de ^{3}H-dexametasona (el ligando específico para el receptor de glucocorticoides).For Table 4, fractions of cerebral cytosol as for Table 3 and the compounds were incubated with 3 nM of 3 H-dexamethasone (the ligand specific for the glucocorticoid receptor).
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La Tabla 5 muestra la inhibición de la unión de ^{3}H-estradiol (el ligando específico para el receptor de estrógenos) a citosol de útero bovino, preparado como se describe previamente (Gee y otros, Journal of Pharmacology and Experimental Therapeutics 246:803-812 (1988)). Se incubó ^{3}H-estradiol (0,15 nM) con el citosol en presencia de los compuestos.Table 5 shows the inhibition of the binding of 3 H-estradiol (the estrogen receptor-specific ligand) to bovine uterine cytosol, prepared as previously described (Gee et al., Journal of Pharmacology and Experimental Therapeutics 246 : 803-812 (1988)). 3 H-estradiol (0.15 nM) was incubated with the cytosol in the presence of the compounds.
Los resultados de estos experimentos muestran claramente que los esteroides neuroactivos no tienen una afinidad fuerte para ninguno de los receptores de esteroides mencionados previamente. Así, no tendrán los efectos secundarios hormonales que estarían asociados con la unión a tales receptores de esteroides. El esteroide neuroactivo, 3\alpha-hidroxi-3\beta-metil-5\alpha-pregnan-20-ona, se probó adicionalmente in vivo y también se encontró que no tenía actividad hormonal cuando se administraba a animales in vivo.The results of these experiments clearly show that neuroactive steroids do not have a strong affinity for any of the steroid receptors mentioned previously. Thus, they will not have the hormonal side effects that would be associated with binding to such steroid receptors. The neuroactive steroid, 3α-hydroxy-3β-methyl-5α-pregnan-20-one, was further tested in vivo and was also found to have no hormonal activity when administered to animals in vivo .
También se realizaron experimentos para determinar la relevancia fisiológica de interacciones de receptores de esteroides neuroactivos y GABA determinando la capacidad de los compuestos de la presente invención para prevenir convulsiones inducidas por metrazol en ratones. Los ratones fueron inyectados con diversas dosis de los compuestos de prueba de la invención, 10 minutos antes de la inyección de metrazol. El tiempo hasta el comienzo de mioclonía (presencia de actividad clónica de las patas traseras) inducida por metrazol se determinó observando cada ratón durante un período de 30 minutos. En ratones de control, el metrazol (85 mg/kg) inducirá la convulsión en 95% de los animales. La capacidad de varios compuestos de la presente invención para proteger a los ratones de la convulsión se muestra en la Tabla 6.Experiments were also performed to determine the physiological relevance of receptor interactions of neuroactive steroids and GABA determining the ability of compounds of the present invention to prevent seizures induced by metrazole in mice. The mice were injected with various doses of the test compounds of the invention, 10 minutes before metrazole injection. The time until beginning of myoclonus (presence of clone activity of the legs rear) induced by metrazole was determined by observing each mouse over a period of 30 minutes. In control mice, the Metrazol (85 mg / kg) will induce seizure in 95% of animals. The ability of various compounds of the present invention to Protect mice from seizure shown in Table 6.
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La capacidad de esteroides neuroactivos sintéticos para proteger a los animales contra otros convulsivos químicos se demostró además para varios compuestos de la presente invención. Las pruebas anticonvulsivas son similares a la descrita previamente. Se emplearon los siguientes convulsivos químicos: metrazol (85 mg/kg); suculina (2,7 mg/kg); picrotoxina (3,15 mg/kg); estricnina (1,25 mg/kg) o vehículo (solución salina al 0,9%). Inmediatamente después de la inyección del convulsivo o el vehículo, los ratones se observaron durante un período de 30 a 45 minutos. Se registró el número de animales con convulsiones tónicas y/o clónicas. En la prueba de electrochoque máximo, 50 mA de corriente a 60 Hz se aportaron a través de electrodos corneales durante 200 milisegundos para inducir el ataque tónico. La capacidad de los compuestos para eliminar el componente tónico se definió como el punto final. El potencial de depresión de SNC general se determinó mediante una prueba en rodillo giratorio 10 minutos después de la inyección de compuestos, donde se determinó el número de ratones que permanecían sobre un rodillo giratorio (6 rpm) durante 1 minuto en uno de los tres experimentos. Las ED_{50}'s (la dosis a la que se produce el efecto semimáximo) se determinaron para cada rastreo y se presentan en la Tabla 7, más adelante. Los resultados demuestran que los esteroides neuroactivos, en comparación con otros anticonvulsivos clínicamente útiles, son altamente eficaces con perfiles similares al de la BZ clonazepam. Estas observaciones demuestran la utilidad terapéutica de estos compuestos como moduladores de la excitabilidad cerebral, que está en correspondencia con su alta interacción de afinidad con el GRC in vitro.The ability of synthetic neuroactive steroids to protect animals against other chemical seizures was further demonstrated for various compounds of the present invention. The anticonvulsant tests are similar to the one described previously. The following chemical seizures were used: metrazole (85 mg / kg); suculin (2.7 mg / kg); picrotoxin (3.15 mg / kg); Strychnine (1.25 mg / kg) or vehicle (0.9% saline). Immediately after injection of the seizure or vehicle, the mice were observed for a period of 30 to 45 minutes. The number of animals with tonic and / or clonic seizures was recorded. In the maximum electro-shock test, 50 mA of current at 60 Hz was supplied through corneal electrodes for 200 milliseconds to induce the tonic attack. The ability of the compounds to eliminate the tonic component was defined as the end point. The general CNS depression potential was determined by a rotating roller test 10 minutes after compound injection, where the number of mice that remained on a rotating roller (6 rpm) for 1 minute in one of the three experiments was determined. . The ED50s (the dose at which the semi-maximum effect occurs) were determined for each screening and are presented in Table 7, below. The results show that neuroactive steroids, compared to other clinically useful anticonvulsants, are highly effective with profiles similar to that of BZ clonazepam. These observations demonstrate the therapeutic utility of these compounds as modulators of brain excitability, which corresponds to their high affinity interaction with the in vitro GRC.
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Los siguientes experimentos demuestran que los compuestos de la presente invención son ansiolíticos eficaces en dos modelos animales de ansiedad humana que miden los efectos sobre el comportamiento de compuestos ansiolíticos. Datos sobre otros compuestos de la presente invención en estas medidas se presentan en las Tablas 8 y 9. Los dos modelos animales usados para medir los efectos sobre el comportamiento de compuestos ansiolíticos son la prueba del laberinto elevado en forma de signo más y la prueba de conflictos de Geller-Seifter.The following experiments show that Compounds of the present invention are anxiolytic effective in two animal models of human anxiety that measure the effects on the behavior of anxiolytic compounds. Facts about others Compounds of the present invention in these measurements are presented in Tables 8 and 9. The two animal models used to measure the effects on the behavior of anxiolytic compounds are the elevated maze test in the form of a plus sign and the proof of Geller-Seifter conflicts.
La base teórica para la prueba del laberinto en forma de signo más es similar a la de la prueba de transición luz/oscuridad. Según fue descrito previamente por Pellow y otros, J. Neurosci. Meth. 14:149-167 (1985)), el aparato del laberinto elevado en forma de signo más se diseña para utilizar la aversión natural de los ratones a los espacios abiertos. El aparato consiste en dos brazos abiertos y dos brazos cerrados. La prueba del laberinto elevado en forma de signo más permite dos medidas de ansiedad, el número de entradas en los brazos abiertos y el tiempo transcurrido en los brazos abiertos, ambos expresados como un porcentaje del número total de entradas y el tiempo transcurrido en/sobre tanto los brazos abiertos como los brazos cerrados.The theoretical basis for the plus-shaped maze test is similar to that of the light / dark transition test. As previously described by Pellow et al., J. Neurosci. Meth. 14 : 149-167 (1985)), the raised labyrinth apparatus in the form of a plus sign is designed to use the natural aversion of mice to open spaces. The apparatus consists of two open arms and two closed arms. The elevated labyrinth test in the form of a plus sign allows two measures of anxiety, the number of entries in the open arms and the time spent in the open arms, both expressed as a percentage of the total number of entries and the time spent in / on both open arms and closed arms.
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Ratones Swiss-Webster N.I.H. macho (Harlam, Indianapolis, IN) que pesaban 15-20 g se alojaron cuatro por jaula en jaulas de polietileno con lecho de serrín. La cámara de cría se controló medioambientalmente (22ºC) con un ciclo de 12 horas de luz/oscuridad (0600-1800 horas). El agua y la comida estaban disponibles a voluntad, excepto durante la prueba. Los experimentos se realizaron de 0700-1500 horas y los grupos se contrarrestaron con respecto a los efectos del día. A los animales solo se les administró fármaco o vehículo una vez.Swiss-Webster N.I.H. male (Harlam, Indianapolis, IN) weighing 15-20 g four were housed per cage in polyethylene cages with bedding sawdust. The breeding chamber was controlled environmentally (22ºC) with a 12 hour light / dark cycle (0600-1800 hours). Water and food were available at will, except during the test. The experiments they were made from 0700-1500 hours and the groups were They countered with respect to the effects of the day. To the animals They were only given drug or vehicle once.
El método usado fue descrito previamente (Lister, Psychopharmacol. 92:180-185 (1987)). El aparato incluía dos brazos abiertos perpendiculares a dos brazos cerrados elevados 50 cm del suelo. Cada brazo tenia 50 cm de longitud y las paredes de los brazos cerrados tenían 40 cm de alto. El laberinto estaba realizado completamente de plexiglás negro. Lámparas de luz incandescente de 200 W estaban por encima de cada uno de los brazos abiertos para producir un fuerte contraste entre los brazos abiertos y los brazos cerrados.The method used was previously described (Lister, Psychopharmacol. 92: 180-185 (1987)). The apparatus included two open arms perpendicular to two closed arms raised 50 cm from the floor. Each arm was 50 cm long and the walls of the closed arms were 40 cm high. The labyrinth was made entirely of black plexiglass. 200 W incandescent light lamps were above each of the open arms to produce a strong contrast between the open arms and the closed arms.
Diez minutos después de una inyección, los ratones Swiss-Webster N.I.H. se pusieron en el centro del laberinto en forma de signo más de cara a un brazo abierto. Durante el período de prueba de 5 minutos, se midió el número de entradas en los brazos abiertos y los brazos cerrados y el tiempo transcurrido en los brazos abiertos y los brazos cerrados. Las cuatro patas tenían que estar dentro de un brazo para que la variable dependiente se midiera. Por lo tanto, el tiempo transcurrido en el centro del laberinto no se cuenta, de modo que el tiempo total transcurrido en los brazos abiertos y los brazos cerrados no puede ser igual a 5 minutos.Ten minutes after an injection, the Swiss-Webster N.I.H. they put in the center of the maze in the form of a plus sign facing one arm open. During the 5 minute test period, the number of entries in open arms and closed arms and the time spent in open arms and arms closed. The four legs had to be inside one arm to that the dependent variable be measured. Therefore time elapsed in the center of the maze is not counted, so that the total time spent in open arms and arms closed cannot be equal to 5 minutes.
La Tabla 8 muestra el resumen de las actividades ansiolíticas de compuestos de la presente invención usando el laberinto elevado en forma de signo más bajo las mismas condiciones descritas previamente.Table 8 shows the summary of the activities Anxiolytics of compounds of the present invention using the raised maze in the form of a plus sign under the same conditions previously described.
Este modelo animal de ansiedad humana utiliza un estado condicional de conflicto en ratas para determinar las propiedades ansiolíticas de fármacos. Las ratas se acondicionan para la presión de la barra para el refuerzo positivo bajo dos esquemas de comportamiento (Geller y Seifter, Psychopharmacologia 1:482-492 (1960)). El primero incluye una presión de la barra bajo un esquema de relaciones variables sin castigo. El segundo componente es un esquema de relaciones fijas dando como resultado cada presión de la barra un refuerzo positivo y un castigo. El componente castigado produce un estado de conflicto dentro del animal. El componente no castigado permite la observación de cualesquiera efectos depresivos de respuesta que pueda poseer un fármaco. Una respuesta ansiolítica incrementaría la respuesta castigada sin afectar a la respuesta no castigada.This animal model of human anxiety uses a conditional state of conflict in rats to determine the anxiolytic properties of drugs. Rats are conditioned for bar pressure for positive reinforcement under two behavior schemes (Geller and Seifter, Psychopharmacology 1 : 482-492 (1960)). The first includes a pressure of the bar under a scheme of variable relationships without punishment. The second component is a fixed relationship scheme resulting in each bar pressure positive reinforcement and punishment. The punished component produces a state of conflict within the animal. The non-punished component allows observation of any depressive response effects that a drug may possess. An anxiolytic response would increase the punished response without affecting the non-punished response.
Ratas Sprague-Dawley albinas macho (Charles River Labs, Wilmington, MA) que pesaban 250-300 g se usaron para experimentos de conflicto y se mantuvieron con una dieta estricta de nódulos alimenticios de Purina Lab Chow con agua disponible en todo momento para mantener el peso corporal a 85% de sus niveles de adultos jóvenes que se alimentan libremente. Las ratas fueron alojadas individualmente bajo un ciclo de luz-oscuridad de 12 horas con luces de 0700-1900.Albra Sprague-Dawley Rats male (Charles River Labs, Wilmington, MA) weighing 250-300 g were used for conflict experiments and they maintained a strict diet of food nodules of Purina Lab Chow with water available at all times to maintain body weight at 85% of your young adult levels that feed freely. The rats were housed individually under a 12-hour light-dark cycle with lights from 0700-1900.
Los efectos antiansiedad (rebajador de castigo) y
depresor de la respuesta de los compuestos de la presente invención
se midieron en ratas mediante la prueba de conflicto de Geller y
Seifter. En esta prueba de 63 minutos, las ratas hambrientas
realizan una respuesta de presión de la palanca para obtener una
recompensa de leche endulzada. El esquema de refuerzo consiste en
componentes de castigo y no castigo, que se alternan
aproximadamente cada 15 minutos. Las ratas fueron entrenadas en
cámaras de prueba (instrumentos de Coulbourn) con una palanca
montada en una pared, un pequeño cazo que aportaba los 0,1 ml de
recompensa de leche (1 parte de leche condensada Eagle:2 partes de
agua) y un suelo de tela metálica a través del cual se administraba
el castigo en forma de electrochoque en las patas. Se usó un
miniordenador DEC PDP 11/73 que desarrollaba SKED (State Systems)
para programar y
registrar.The anti-aging effects (punishment reducer) and depressor of the response of the compounds of the present invention were measured in rats by the Geller and Seifter conflict test. In this 63-minute test, the hungry rats perform a lever pressure response to obtain a reward of sweetened milk. The reinforcement scheme consists of punishment and non-punishment components, which alternate approximately every 15 minutes. The rats were trained in test chambers (Coulbourn instruments) with a lever mounted on a wall, a small saucepan that provided the 0.1 ml milk reward (1 part of Eagle condensed milk: 2 parts of water) and a wire mesh floor through which the punishment was administered in the form of an electric shock in the legs. A DEC PDP 11/73 minicomputer that was developed by SKED (State Systems) was used to program and
to register.
Las ratas aprendían inicialmente a responder sobre un esquema de refuerzo continuo y progresaban rápidamente hasta esquemas de intervalos variables (IV) de 30 segundos, 1 minuto y 2 minutos. Sobre el esquema de refuerzo continuo, las ratas recibían recompensa de leche después de cada presión de la palanca. En los esquemas IV, las recompensas de leche estaban disponibles a intervalos infrecuentes y variables, finalmente en una media de una vez cada dos minutos. Se introdujeron a continuación cuatro períodos de "conflicto" de 3 minutos en la línea de base IV no castigada. El primero comenzaba después de 3 minutos de comportamiento IV y los otros se alternaban entre períodos de 12 minutos de respuesta IV. Durante los períodos de conflicto, que eran señalados por la presentación de una luz y un tono, el esquema de refuerzo continuo estaba de nuevo en vigor y cada presión de la palanca suministraba tanto una recompensa de leche como un breve (0,25 milisegundos) castigo en forma de electrochoque en las patas. La intensidad del electrochoque era 0,2 mA inicialmente y se incrementó diariamente en incrementos de 0,02 mA para suprimir gradualmente la presión de la palanca hasta 5 respuestas o menos por período de conflicto. Este entrenamiento lleva 4-6 semanas, después de las cuales se observaron grados bajos estables de respuesta durante períodos de conflicto y grados altos estables en los períodos sin castigo. Los incrementos inducidos por fármaco en el grado de respuestas castigadas se tomaron como un índice de la actividad antiansiedad, mientras que las disminuciones en el grado de respuestas no castigadas se tomaron como un índice de depresión de la respuesta o sedación.Rats initially learned to respond on a continuous reinforcement scheme and progressed rapidly up to 30 second variable interval (IV) schemes, 1 minute and 2 minutes. On the continuous reinforcement scheme, the rats received milk reward after each pressure of the lever. In Schemes IV, milk rewards were available at infrequent and variable intervals, finally in An average of once every two minutes. They were introduced to then four periods of "conflict" of 3 minutes in the Baseline IV not punished. The first began after 3 minutes of behavior IV and the others alternated between 12 minute response periods IV. During periods of conflict, which were signaled by the presentation of a light and a tone, the continuous reinforcement scheme was again in force and each lever pressure provided both a reward of milk as a brief (0.25 milliseconds) punishment in the form of electric shock in the legs. The intensity of the electric shock was 0.2 mA initially and increased daily in 0.02 increments mA to gradually suppress lever pressure up to 5 responses or less per period of conflict. This training it takes 4-6 weeks, after which it observed stable low degrees of response during periods of stable conflict and high grades in periods without punishment. The drug-induced increases in the degree of responses punished were taken as an index of anti-aging activity, while decreases in the degree of responses do not punished were taken as an index of depression of the response or sedation.
La Tabla 9 muestra el resumen de actividades ansiolíticas de un compuesto en la prueba de Geller-Seifter bajo las condiciones experimentales descritas previamente. Se espera asimismo que los restantes compuestos de la presente invención produzcan incrementos en el grado de respuestas castigadas en la prueba de Geller-Seifter, y se espera que posean actividad ansiolítica.Table 9 shows the summary of activities anxiolytics of a compound in the test of Geller-Seifter under experimental conditions previously described. The remaining ones are also expected Compounds of the present invention produce increases in the degree of responses punished in the test of Geller-Seifter, and are expected to possess activity anxiolytic
La actividad anticonvulsiva de un profármaco (éster 3\alpha-isobutírico) del compuesto básico 3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano se muestra en la figura 1.The anticonvulsant activity of a prodrug (3α-isobutyric ester) of the basic compound 3α-hydroxy-17β-methoxy-5α-androstane It is shown in figure 1.
El porcentaje de protección de este profármaco de 3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano contra ataques inducidos por metanol se representó frente al tiempo después de la administración de los compuestos (figura 1). Se entiende que este compuesto se usa como un ejemplo experimental para ilustrar la utilidad de profármacos.The protection percentage of this prodrug of 3α-hydroxy-17β-methoxy-5α-androstane against methanol-induced attacks was represented against the time after administration of the compounds (figure 1). Be understand that this compound is used as an experimental example to illustrate the usefulness of prodrugs.
En contraste con las benzodiazepinas, los esteroides neuroactivos también pueden inducir la anestesia. Se cree que su capacidad para inducir la anestesia se debe a su capacidad para abrir el canal de iones cloruro en ausencia de GABA, que es una propiedad no poseída por las benzodiazepinas. Por lo tanto, los neuroesteroides pueden actuar directamente en ausencia de GABA, en el receptor, y también "indirectamente", en presencia de GABA. Esta acción "indirecta" se denomina "modular" el receptor. Lambert y otros, Trends Pharmacology Science 8:224-227 (1987).In contrast to benzodiazepines, neuroactive steroids can also induce anesthesia. Its ability to induce anesthesia is believed to be due to its ability to open the chloride ion channel in the absence of GABA, which is a property not owned by benzodiazepines. Therefore, neurosteroids can act directly in the absence of GABA, in the recipient, and also "indirectly", in the presence of GABA. This "indirect" action is called the "modular" receiver. Lambert et al., Trends Pharmacology Science 8 : 224-227 (1987).
Los compuestos de y usados en la invención también pueden usarse para indicaciones anestésicas en altas dosis. Sin embargo, la ruta preferida de administración para inducir la anestesia es la administración intravenosa (i.v.). En animales, una propiedad anestésica de un fármaco se mide mediante la capacidad del fármaco para producir un reflejo de pérdida de enderezamiento. El reflejo de pérdida de enderezamiento se define como la incapacidad de un animal para enderezarse en 30 segundos cuando se pone sobre su lomo. A los ratones se les administró fármaco i.v. en la vena de la cola lateral. Después de la administración, los ratones se pusieron sobre sus lomos y se observó el reflejo de pérdida de enderezamiento. Resultados ilustrativos se presentan en la Tabla 10.The compounds of and used in the invention They can also be used for anesthetic indications in high doses. However, the preferred route of administration to induce Anesthesia is intravenous administration (i.v.). In animals, one anesthetic property of a drug is measured by the ability of the drug to produce a reflection of straightening loss. The loss of straightening reflex is defined as the inability of an animal to straighten in 30 seconds when puts on his back. The mice were administered drug i.v. in the vein of the lateral tail. After administration, the mice were placed on their loins and the reflex of loss of straightening. Illustrative results are presented in Table 10
Se anticipa que los profármacos, con modificaciones similares a las que se describen previamente, de los compuestos de y usados en la invención tendrán actividad como profármacos.It is anticipated that the prodrugs, with modifications similar to those described previously, of the compounds of and used in the invention will have activity as prodrugs
Habiendo descrito ahora completamente esta invención, será entendido por los expertos normales en la especialidad que la misma puede realizarse dentro de una gama amplia y equivalente de condiciones, formulaciones y otros parámetros sin afectar al alcance de la invención o cualquier modalidad de la misma. Todas las patentes y publicaciones citadas aquí se incorporan completamente mediante referencia en su totalidad.Having now fully described this invention, will be understood by normal experts in the specialty that can be done within a range broad and equivalent conditions, formulations and others parameters without affecting the scope of the invention or any modality of it. All patents and publications cited here they are fully incorporated by reference in their whole.
Claims (31)
3\beta-(4'-dimetilaminofenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano; 3\beta-(4'-acetilfenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano; 3\beta-(4'-clorofenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano; 3\beta-(4'-acetilfenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano; éster etílico de 3\beta-(4'-carboxifeniletinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano; 3\alpha-hidroxi-3\beta-(4'-acetoxiacetilfenil)fenil))etinil-17\beta-metoxi-5\beta-androstano o 3\beta-(4'-cianofenil)etinil-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano.5. A compound according to claim 4, which is 3α-hydroxy-3β- (4'-nitrophenyl) ethynyl-17β-methoxy-5β-androstane; 3α-hydroxy-3β- (4'-methoxyphenyl) ethynyl-17β-methoxy-5β-androstane; 3α-hydroxy-3β- [2- (3 ', 4'-dimethoxyphenyl) ethyl] -17β-methoxy-5β-androstane; 3α-hydroxy-3β- (4'-methylphenyl) ethynyl-17β-methoxy-5β-androstane; 3β- (4'-trifluoromethylphenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3α-hydroxy-3β- (2'-methoxyphenyl) ethynyl-17β-methoxy-5β-androstane;
3β- (4'-dimethylaminophenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-acetylphenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-chlorophenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-acetylphenyl) ethynyl-3α-hydroxy-17β-methoxy-5α-androstane; 3β- (4'-carboxyphenylenyl) -3α-hydroxy-17β-methoxy-5β-androstane ethyl ester; 3α-hydroxy-3β- (4'-acetoxyacetylphenyl) phenyl)) ethynyl-17β-methoxy-5β-androstane or 3β- (4'-cyanophenyl) ethynyl-3α-hydroxy -17? -Methoxy-5? -Androstane.
sal sódica de 6'-hemisuccinato de 3\beta-(6'-hidroxi-1'-hexinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano; 3\beta-(4'-hidroxi-1'-butinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano; sal sódica de 4'-hemisuccinato de 3\beta-(4'-hidroxi-1'-butinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano; 3\beta-(4'-hidroxi-1'-butinil)-3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano; sal sódica de 4'-hemisuccinato de 3\beta-(4'-hidroxi-1'-butinil)-3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano; 3\beta-(4'-hidroxi-1'-butinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-19-norandrostano; sal sódica de 4'-hemisuccinato de 3\beta-(4'-hidroxi-1'-butinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-19-norandrostano; 3\beta-[3'(R/S)-hidroxi-1'-butinil)-3\alpha-hidroxi-17\beta-metoxi-5\alpha-androstano o 3\beta-(3'-hidroxi-1'-propinil)-3\alpha-hidroxi-17\beta-metoxi-5\beta-androstano.10. A compound according to claim 9, which is 3α-hydroxy-3β- (5'-cyano-1'-pentinyl) -17β-methoxy-5β-androstane; 3α-hydroxy-3β- (4'-cyano-1'-butynyl) -17β-methoxy-5β-androstane; 3α-hydroxy-3β- [6'-oxo-1'-heptinyl] -17β-methoxy-5β-androstane; 3α-hydroxy-3β- (7'-oxo-1'-octinyl) -17β-methoxy-5β-androstane; 3α-hydroxy-3β- (5'-oxo-1'-hexinyl) -17β-methoxy-5β-androstane; 3α-hydroxy-3β- (5'-oxo-1'-pentinyl) -17β-methoxy-5β-androstane; 3β- (4 '(R / S) -hydroxipentinyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3β- [5 '- (R / S) -hydroxyhexinyl] -3α-hydroxy-17β-methoxy-5β-androstane; 3β- (5'-hydroxy-1'-pentinyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3β- (5'-hydroxy-1'-pentinyl) -3α-hydroxy-17β-methoxy-5β-androstane hemisuccinate sodium salt; 3β- (6'-hydroxy-1'-hexinyl) -3α-hydroxy-17β-methoxy-5β-androstane;
3'- (6'-hydroxy-1'-hexinyl) -3α-hydroxy-17β-methoxy-5β-androstane 6'-hemisuccinate sodium salt; 3β- (4'-hydroxy-1'-butynyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3'- (4'-hydroxy-1'-butynyl) -3α-hydroxy-17β-methoxy-5β-androstane 4'-hemisuccinate sodium salt; 3β- (4'-hydroxy-1'-butynyl) -3α-hydroxy-17β-methoxy-5α-androstane; 3'- (4'-hydroxy-1'-butynyl) -3α-hydroxy-17β-methoxy-5α-androstane 4'-hemisuccinate sodium salt; 3β- (4'-hydroxy-1'-butynyl) -3α-hydroxy-17β-methoxy-5β-19-norandrostane; 3'- (4'-hydroxy-1'-butynyl) -3α-hydroxy-17β-methoxy-5β-19-norandrostane 4'-hemisuccinate sodium salt; 3β- [3 '(R / S) -hydroxy-1'-butynyl) -3α-hydroxy-17β-methoxy-5α-androstane or 3β- (3'-hydroxy-1 '-propyl) -3α-hydroxy-17β-methoxy-5β-androstane.
17\beta-metoxi-5\alpha-androstano.12. A compound according to claim 11, which is 3β- (3'-acetoxy-1'-propynyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-acetoxy-1'-butynyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-acetoxy-1'-butynyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3β- (5'-acetoxy-1'-pentinyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3β- (6'-acetoxy-1'-hexinyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3α-hydroxy-3β- [3- (2'-propynyloxy) -1-propynyl] -17β-methoxy-5β-androstane; 3α-hydroxy-3β- (3-methoxy-1-propynyl) -17β-methoxy-5β-androstane or 3α-hydroxy-3β- (3-methoxy-1-propynyl) ) -
17β-methoxy-5α-androstane.
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ES96919372T Expired - Lifetime ES2235187T3 (en) | 1995-06-06 | 1996-06-06 | NEUROACTIVE STEROIDS OF THE ANDROSTAN AND PREGNAN SERIES. |
Country Status (23)
Country | Link |
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US (1) | US5925630A (en) |
EP (2) | EP1288220A3 (en) |
JP (1) | JP4145350B2 (en) |
KR (1) | KR19990022323A (en) |
CN (1) | CN1190404A (en) |
AT (1) | ATE284895T1 (en) |
AU (1) | AU725214B2 (en) |
BR (1) | BR9608592A (en) |
CA (1) | CA2223996A1 (en) |
CZ (1) | CZ394197A3 (en) |
DE (1) | DE69634039T2 (en) |
ES (1) | ES2235187T3 (en) |
FI (1) | FI974448A (en) |
GE (1) | GEP20012530B (en) |
HU (1) | HUP9901138A3 (en) |
IL (1) | IL122348A0 (en) |
NO (1) | NO311805B1 (en) |
NZ (1) | NZ310850A (en) |
PL (1) | PL185523B1 (en) |
PT (1) | PT837874E (en) |
RU (1) | RU2194712C2 (en) |
UA (1) | UA57706C2 (en) |
WO (1) | WO1996040043A2 (en) |
Families Citing this family (93)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070129282A1 (en) * | 1998-11-24 | 2007-06-07 | Ahlem Clarence N | Pharmaceutical treatments and compositions |
WO2000050034A1 (en) * | 1999-02-24 | 2000-08-31 | The Regents Of The University Of California | Gaba receptors mediate inhibition of t cell responses |
WO2000066614A1 (en) * | 1999-04-29 | 2000-11-09 | Purdue Pharma Ltd. | 3α-HYDROXY-3β METHOXYMETHYL-21-HETEROCYCLE SUBSTITUTED STEROIDS WITH ANESTHETIC ACTIVITY |
EP1449846A1 (en) * | 1999-04-29 | 2004-08-25 | Euro-Celtique S.A. | 3-alpha Hydroxy-3-beta methoxymethyl-21-heterocycle substituted steriods with anaesthetic activity |
CA2670236C (en) * | 1999-09-30 | 2012-06-05 | Hollis-Eden Pharmaceuticals, Inc. | Therapeutic treatment of androgen receptor driven conditions |
GB2363984A (en) * | 2000-06-29 | 2002-01-16 | Hunter Fleming Ltd | Protection against neuronal damage using 3-hydroxy-7 -hydroxy steroids and 3-oxo-7 -hydroxy steroids |
GB2363983A (en) | 2000-06-29 | 2002-01-16 | Hunter Fleming Ltd | Protection against neuronal damage using 7-hydroxyepiandrosterone |
US20020072509A1 (en) * | 2000-10-11 | 2002-06-13 | Stein Donald Gerald | Methods for the treatment of a traumatic central nervous system injury |
AR031473A1 (en) * | 2000-11-20 | 2003-09-24 | Lundbeck & Co As H | GABA INTENSIFIERS IN THE TREATMENT OF DISEASES RELATED TO A REDUCED NEUROSTEROID ACTIVITY |
GR1003861B (en) * | 2000-12-29 | 2002-04-11 | Novel gabaa modulating neurosteroids | |
EP2135611A1 (en) | 2001-03-01 | 2009-12-23 | Hollis-Eden Pharmaceuticals Inc. | Pregn-5-en-20-yne-3,7,17-triol derivatives for use in therapy |
US8569275B2 (en) | 2002-08-28 | 2013-10-29 | Harbor Therapeutics, Inc. | Steroids having 7-oxgen and 17-heteroaryl substitution |
EP1615944A4 (en) * | 2003-04-01 | 2010-08-11 | Harbor Biosciences Inc | Antiandrogens with marginal agonist activity and methods of use |
US7795266B2 (en) * | 2003-09-25 | 2010-09-14 | Helton David R | Tetrahydroindolone derivatives for treament of neurological conditions |
US20050107439A1 (en) * | 2003-11-10 | 2005-05-19 | Helton David R. | Composition and method for treating emesis |
WO2006012563A2 (en) * | 2004-07-23 | 2006-02-02 | The Regents Of The University Of California | Method for the treatment and diagnosis of certain psychiatric disorders related to the menstrual cycle |
CA2582231A1 (en) | 2004-09-29 | 2006-10-19 | Hollis-Eden Pharmaceuticals, Inc. | Steroid analogs and uses |
US20060211667A1 (en) * | 2005-03-21 | 2006-09-21 | Eric Marchewitz | Use of pregnane steroid derivatives for enhancing physical performance |
EP1868614B1 (en) * | 2005-03-24 | 2012-08-08 | Emory University | Dosage regimen for the treatment of a traumatic brain injury with progesterone |
US7473687B2 (en) * | 2005-03-24 | 2009-01-06 | Emory University | Methods for the treatment of a traumatic central nervous system injury |
EP2258358A3 (en) | 2005-08-26 | 2011-09-07 | Braincells, Inc. | Neurogenesis with acetylcholinesterase inhibitor |
CA2620333A1 (en) | 2005-08-26 | 2007-03-01 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation |
EP1940389A2 (en) | 2005-10-21 | 2008-07-09 | Braincells, Inc. | Modulation of neurogenesis by pde inhibition |
CA2625210A1 (en) * | 2005-10-31 | 2007-05-10 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
AU2007249399A1 (en) | 2006-05-09 | 2007-11-22 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
MX2008014320A (en) | 2006-05-09 | 2009-03-25 | Braincells Inc | 5 ht receptor mediated neurogenesis. |
MX2009002496A (en) | 2006-09-08 | 2009-07-10 | Braincells Inc | Combinations containing a 4-acylaminopyridine derivative. |
PL2097437T3 (en) * | 2006-11-21 | 2015-12-31 | Umecrine Cognition Ab | The use of pregnane and androstane steroids for the manufacture of a pharmaceutical composition for the treatment of cns disorders |
US20100204192A1 (en) | 2007-06-11 | 2010-08-12 | University Of Sourthern California | Agents, compositions and methods for enhancing neurological function |
WO2008154579A1 (en) * | 2007-06-11 | 2008-12-18 | University Of Southern California | Allopregnanolone in a method for enhancing neurological function (alzheimer disease) |
WO2009062134A1 (en) * | 2007-11-09 | 2009-05-14 | Cenomed Biosciences, Llc | Treatment of post-traumatic stress disorder with tetrahydroindolone arylpiperazine compounds |
US20090264443A1 (en) * | 2008-04-18 | 2009-10-22 | David Helton | Treatment of organophosphate exposure with tetrahydroindolone arylpiperazine compounds |
CN101585862B (en) * | 2008-05-20 | 2014-12-17 | 梅克芳股份公司 | Novel steroids |
US20100216805A1 (en) | 2009-02-25 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
WO2012050907A2 (en) | 2010-09-28 | 2012-04-19 | The Regents Of The University Of California | Gaba agonists in the treatment of disorders associated with metabolic syndrome and gaba combinations in treatment or prophylaxis of type i diabetes |
WO2012116290A2 (en) | 2011-02-25 | 2012-08-30 | Washington University | Neuroactive 17(20)-z-vinylcyano-substituted steroids, prodrugs thereof, and methods of treatment using same |
WO2013019711A2 (en) * | 2011-07-29 | 2013-02-07 | The Regents Of The University Of California | NOVEL 17β-HETEROARYL-SUBSTITUTED STEROIDS AS MODULATORS OF GABAA RECEPTORS |
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US20130281418A1 (en) * | 2012-04-23 | 2013-10-24 | Eric D. Marchewitz | Use of hydroxypregnenolone derivatives for enhancing health and physical performance |
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US10202413B2 (en) | 2013-02-15 | 2019-02-12 | Washington University | Neuroactive enantiomeric 15-, 16- and 17-substituted steroids as modulators for GABA type-A receptors |
US9512170B2 (en) | 2013-03-01 | 2016-12-06 | Washington University | Neuroactive 13, 17-substituted steroids as modulators for GABA type-A receptors |
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WO2014160480A1 (en) | 2013-03-13 | 2014-10-02 | Sage Therapeutics, Inc. | Neuroactive steroids and methods of use thereof |
US9562026B2 (en) | 2013-03-14 | 2017-02-07 | Washington University | Neuroactive substituted cyclopent[a]anthracenes as modulators for GABA type-A receptors |
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US9725481B2 (en) | 2013-04-17 | 2017-08-08 | Sage Therapeutics, Inc. | 19-nor C3, 3-disubstituted C21-C-bound heteroaryl steroids and methods of use thereof |
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US20160068563A1 (en) | 2013-04-17 | 2016-03-10 | Boyd L. Harrison | 19-nor neuroactive steroids and methods of use thereof |
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WO2015195962A1 (en) | 2014-06-18 | 2015-12-23 | Sage Therapeutics, Inc. | Neuroactive steroids, compositions, and uses thereof |
EP4306114A1 (en) | 2014-06-18 | 2024-01-17 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
WO2016036724A1 (en) | 2014-09-02 | 2016-03-10 | The Texas A&M University System | Method of treating organophosphate intoxication |
ES2808855T3 (en) | 2014-10-16 | 2021-03-02 | Sage Therapeutics Inc | Compositions and methods for treating CNS disorders |
TW202235090A (en) | 2014-10-16 | 2022-09-16 | 美商賽吉醫療公司 | Compositions and methods for treating cns disorders |
WO2016082789A1 (en) | 2014-11-27 | 2016-06-02 | Sage Therapeutics, Inc. | Compositions and methods for treating cns disorders |
TWI748936B (en) | 2015-01-12 | 2021-12-11 | 瑞典商優鎂奎認知Ab公司 | Novel compounds |
HUE054092T2 (en) | 2015-01-26 | 2021-08-30 | Sage Therapeutics Inc | Compositions and methods for treating cns disorders |
ES2935476T3 (en) | 2015-02-20 | 2023-03-07 | Sage Therapeutics Inc | Neuroactive steroids, compositions and uses thereof |
IL305404A (en) | 2015-07-06 | 2023-10-01 | Sage Therapeutics Inc | Oxysterols and methods of use thereof |
EP4316591A3 (en) | 2015-07-06 | 2024-04-24 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
US11117924B2 (en) | 2015-07-06 | 2021-09-14 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
WO2017156103A1 (en) | 2016-03-08 | 2017-09-14 | Sage Therapeutics, Inc. | Neuroactive steroids, compositions, and uses thereof |
BR112018070123A2 (en) | 2016-04-01 | 2019-02-05 | Sage Therapeutics Inc | oxiesterós and methods of use thereof |
WO2017193046A1 (en) | 2016-05-06 | 2017-11-09 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
CA3029900A1 (en) | 2016-07-07 | 2018-01-11 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
CA3030420A1 (en) | 2016-07-11 | 2018-01-18 | Sage Therapeutics, Inc. | C7, c12, and c16 substituted neuroactive steroids and their methods of use |
IL264129B2 (en) * | 2016-07-11 | 2024-05-01 | Sage Therapeutics Inc | C17, c20, and c21 substituted neuroactive steroids and their methods of use |
CN106265685A (en) * | 2016-09-18 | 2017-01-04 | 南通大学 | Myrrha sterone Z application in preparing anti-depression drug |
EP3519422B1 (en) | 2016-09-30 | 2022-08-31 | Sage Therapeutics, Inc. | C7 substituted oxysterols and these compounds for use as nmda modulators |
CN115181153A (en) | 2016-10-18 | 2022-10-14 | 萨奇治疗股份有限公司 | Oxysterol and methods of use thereof |
AU2017345399B2 (en) | 2016-10-18 | 2022-02-24 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
WO2019075362A1 (en) * | 2017-10-12 | 2019-04-18 | Sage Therapeutics, Inc. | Method of treating cns disorders with neurosteroids and gabaergic compounds |
MA51568A (en) | 2018-01-12 | 2021-04-21 | Sage Therapeutics Inc | AZA-, OXA AND THIA-PREGNAN-20-ONE-3.ALPHA.-OL COMPOUNDS FOR USE IN THE TREATMENT OF CENTRAL NERVOUS SYSTEM DISORDERS |
CN114805462A (en) * | 2018-02-11 | 2022-07-29 | 江苏豪森药业集团有限公司 | Steroid derivative regulator and preparation method and application thereof |
CN110366555B (en) * | 2018-02-11 | 2021-11-05 | 江苏豪森药业集团有限公司 | Steroid derivative regulator, preparation method and application thereof |
US10562930B1 (en) | 2018-08-31 | 2020-02-18 | Praxis Precision Medicines, Inc. | Salts and crystal forms of GABAA positive allosteric modulator |
WO2020143640A1 (en) * | 2019-01-08 | 2020-07-16 | 成都康弘药业集团股份有限公司 | Steroid compound, and use thereof and preparation method therefor |
BR112021024033A2 (en) * | 2019-05-31 | 2022-02-08 | Sage Therapeutics Inc | Neuroactive steroids and their compositions |
JP2023518411A (en) * | 2020-03-18 | 2023-05-01 | セージ セラピューティクス, インコーポレイテッド | Neuroactive steroids and methods of use thereof |
CA3178758A1 (en) * | 2020-05-18 | 2021-11-25 | Shawn K. SINGH | Treatment of adjustment disorders |
RU2739247C1 (en) * | 2020-09-14 | 2020-12-22 | Общество С Ограниченной Ответственностью "Научно-Технологическая Фармацевтическая Фирма "Полисан" | Method of producing a medicinal preparation for parenteral application |
WO2023060067A1 (en) | 2021-10-04 | 2023-04-13 | Marinus Pharmaceuticals, Inc. | Amorphous solid dispersion ganaxolone formulation |
CA3237550A1 (en) | 2021-11-10 | 2023-05-19 | Umecrine Ab | 3.alpha.-substituted 3.beta.-hydroxy 17-oximated androstane compound for modulation of the alpha-3 subtype of the gaba-a receptor |
WO2023083980A1 (en) | 2021-11-10 | 2023-05-19 | Umecrine Ab | Steroid as a modulator of gabaa receptor |
WO2023083979A1 (en) | 2021-11-10 | 2023-05-19 | Umecrine Ab | 3.beta.-hydroxy, 3.alpha.-ethyl steroids for modulation of the alpha-3 subtype of the gaba-a receptor |
Family Cites Families (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1050765B (en) * | 1959-02-19 | Les Laboratoires Fran?ais de Chimiotherapie, Paris | Process for the preparation of testan-3a-ol-II-one and its esters | |
GB839911A (en) * | 1957-01-29 | 1960-06-29 | Chimiotherapie Lab Franc | Derivatives of etiocholane and the preparation thereof |
US3135744A (en) * | 1961-04-12 | 1964-06-02 | Vismara Francesco Spa | Cycloalkenyl ethers of 17 beta-hydroxy androstanes |
FR1437361A (en) * | 1962-06-28 | 1966-05-06 | Vismara Francesco Spa | Process for the preparation of new alkenyl ethers of 17beta-hydroxy-androstanes |
US3316146A (en) * | 1964-03-30 | 1967-04-25 | Upjohn Co | Method of inducing sedation and muscle relaxation |
GB1376892A (en) * | 1970-11-12 | 1974-12-11 | Glaxo Lab Ltd | 2beta-substituted-3alpha-hydroxysteroids and their esters |
US3943124A (en) * | 1970-12-17 | 1976-03-09 | Gordon Hanley Phillipps | Chemical compounds |
US3953429A (en) * | 1970-12-17 | 1976-04-27 | Glaxo Laboratories Limited | Anaesthetic steroids of the androstance and pregnane series |
US3969345A (en) * | 1970-12-17 | 1976-07-13 | Glaxo Laboratories Limited | 20β,21-Epoxy-3α-hydroxy-5α-pregnanes and derivatives thereof |
GB1380248A (en) * | 1970-12-17 | 1975-01-08 | Glaxo Lab Ltd | 3alpha-hydroxy steroids and esters thereof |
GB1377608A (en) * | 1970-12-17 | 1974-12-18 | Glaxo Lab Ltd | 3alpha-hydroxy or acyloxy pregnene-21-ethers |
GB1409239A (en) * | 1971-11-11 | 1975-10-08 | Glaxo Lab Ltd | Process for the preparation of 3alpha-hydroxy-5alpha-steroids |
GB1432135A (en) * | 1972-05-05 | 1976-04-14 | Glaxo Lab Ltd | 21-substituted pregnanes |
US3959260A (en) * | 1972-05-05 | 1976-05-25 | Glaxo Laboratories Limited | Anaesthetic steroids of the pregnane and 19-norpregnane series having a sulfur-containing group at the 21-position |
GB1436324A (en) * | 1972-05-12 | 1976-05-19 | Glaxo Lab Ltd | Anaesthetic 3alpha-hydroxy pregnanes |
US4192871A (en) * | 1976-01-06 | 1980-03-11 | Glaxo Laboratories Limited | Chemical compounds |
US4197296A (en) * | 1977-03-23 | 1980-04-08 | Glaxo Group Limited | Androstanes |
GB1581235A (en) * | 1977-04-04 | 1980-12-10 | Glaxo Operations Ltd | 11a-amino-3a-hydroxy-steroids |
US4297350A (en) * | 1978-10-10 | 1981-10-27 | The Upjohn Company | Male contraceptive steroids and methods of use |
US5120723A (en) * | 1987-08-25 | 1992-06-09 | University Of Southern California | Method, compositions, and compounds for modulating brain excitability |
US5208227A (en) * | 1987-08-25 | 1993-05-04 | University Of Southern California | Method, compositions, and compounds for modulating brain excitability |
US5319115A (en) * | 1987-08-25 | 1994-06-07 | Cocensys Inc. | Method for making 3α-hydroxy, 3β-substituted-pregnanes |
US5232917A (en) * | 1987-08-25 | 1993-08-03 | University Of Southern California | Methods, compositions, and compounds for allosteric modulation of the GABA receptor by members of the androstane and pregnane series |
AU698834B2 (en) * | 1993-05-24 | 1998-11-12 | Purdue Pharma Ltd. | Methods and compositions for inducing sleep |
IL112638A (en) * | 1994-02-14 | 2003-10-31 | Cocensys Inc | 3alpha-HYDROXYLATED PREGNANE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
CN1171114A (en) * | 1994-11-23 | 1998-01-21 | 科斯赛斯公司 | Androstane and preg nane series for allosteric modulation of gamma-amino-butyric acid receptor |
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1996
- 1996-06-06 ES ES96919372T patent/ES2235187T3/en not_active Expired - Lifetime
- 1996-06-06 NZ NZ310850A patent/NZ310850A/en not_active IP Right Cessation
- 1996-06-06 AT AT96919372T patent/ATE284895T1/en active
- 1996-06-06 JP JP50221097A patent/JP4145350B2/en not_active Expired - Fee Related
- 1996-06-06 AU AU61725/96A patent/AU725214B2/en not_active Ceased
- 1996-06-06 HU HU9901138A patent/HUP9901138A3/en unknown
- 1996-06-06 RU RU98100755/04A patent/RU2194712C2/en not_active IP Right Cessation
- 1996-06-06 US US08/659,192 patent/US5925630A/en not_active Expired - Lifetime
- 1996-06-06 UA UA98010025A patent/UA57706C2/en unknown
- 1996-06-06 CZ CZ973941A patent/CZ394197A3/en unknown
- 1996-06-06 EP EP02025321A patent/EP1288220A3/en not_active Ceased
- 1996-06-06 CA CA002223996A patent/CA2223996A1/en not_active Abandoned
- 1996-06-06 DE DE69634039T patent/DE69634039T2/en not_active Expired - Lifetime
- 1996-06-06 PL PL96323718A patent/PL185523B1/en unknown
- 1996-06-06 WO PCT/US1996/010115 patent/WO1996040043A2/en active IP Right Grant
- 1996-06-06 IL IL12234896A patent/IL122348A0/en not_active IP Right Cessation
- 1996-06-06 PT PT96919372T patent/PT837874E/en unknown
- 1996-06-06 KR KR1019970708803A patent/KR19990022323A/en not_active Application Discontinuation
- 1996-06-06 GE GEAP19964051A patent/GEP20012530B/en unknown
- 1996-06-06 CN CN96195360A patent/CN1190404A/en active Pending
- 1996-06-06 BR BR9608592A patent/BR9608592A/en not_active IP Right Cessation
- 1996-06-06 EP EP96919372A patent/EP0837874B1/en not_active Expired - Lifetime
-
1997
- 1997-12-04 NO NO19975608A patent/NO311805B1/en not_active IP Right Cessation
- 1997-12-05 FI FI974448A patent/FI974448A/en unknown
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